The p.Leu1168GlnfsX5 mutation is the most common mucolipidosis II alpha/beta mutation worldwide and has also been shown to cause Mucolipidosis IIIA in the compound heterozygous state, in combination with mild mutations (Kudo, 2006, summarized in De Pace 2013). This variant has been identified in 0.06% (5/8254) of European American chromosomes and 0.047% (2/4264) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs34002892), consistent with recessive carrier frequencies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1168 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Mucolipidosis II alpha/beta in an autosomal recessive manner.
ClinVar Genomic variation as it relates to human health
NM_024312.5(GNPTAB):c.3503_3504del (p.Leu1168fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(31)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
31
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024312.5(GNPTAB):c.3503_3504del (p.Leu1168fs)
Variation ID: 2771 Accession: VCV000002771.70
- Type and length
-
Microsatellite, 2 bp
- Location
-
Cytogenetic: 12q23.2 12: 101753470-101753471 (GRCh38) [ NCBI UCSC ] 12: 102147248-102147249 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 Sep 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024312.5:c.3503_3504del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077288.2:p.Leu1168fs frameshift NM_024312.5:c.3503_3504delTC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_024312.4:c.3503_3504del NC_000012.12:g.101753470GA[1] NC_000012.11:g.102147248GA[1] NG_021243.1:g.82395TC[1] - Protein change
- L1168fs
- Other names
-
p.Leu1168Glnfs*5
p.Leu1168GlnfsTer5
AY687932:c.3503_3504delTC
- Canonical SPDI
- NC_000012.12:101753469:GAGA:GA
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
Unknown function
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GNPTAB | - | - |
GRCh38 GRCh37 |
1560 | 1581 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (15) |
criteria provided, multiple submitters, no conflicts
|
Sep 22, 2024 | RCV000002899.28 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 24, 2019 | RCV000002900.14 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000082192.45 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000678389.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 15, 2021 | RCV000623507.4 | |
|
GNPTAB-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV004528069.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 25, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
I cell disease
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Study: CSER-MedSeq
Accession: SCV000245616.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015 |
Comment:
The p.Leu1168GlnfsX5 mutation is the most common mucolipidosis II alpha/beta mutation worldwide and has also been shown to cause Mucolipidosis IIIA in the compound heterozygous … (more)
The p.Leu1168GlnfsX5 mutation is the most common mucolipidosis II alpha/beta mutation worldwide and has also been shown to cause Mucolipidosis IIIA in the compound heterozygous state, in combination with mild mutations (Kudo, 2006, summarized in De Pace 2013). This variant has been identified in 0.06% (5/8254) of European American chromosomes and 0.047% (2/4264) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs34002892), consistent with recessive carrier frequencies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1168 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Mucolipidosis II alpha/beta in an autosomal recessive manner. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
GNPTAB-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000375390.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The GNPTAB c.3503_3504delTC (p.Leu1168GlnfsTer5) variant results in a frameshift, and is therefore predicted to result in premature termination of the protein. The variant is well … (more)
The GNPTAB c.3503_3504delTC (p.Leu1168GlnfsTer5) variant results in a frameshift, and is therefore predicted to result in premature termination of the protein. The variant is well described in the literature and is the most common pathogenic variant for for GNPTAB-related disorders in several populations, usually associated with a severe phenotype. Across a selection of the available literature the p.Leu1168GlnfsTer5 variant has been identified in a total of 100 patients with GNPTAB-related disorders, including 51 in a homozygous state, 47 in a compound heterozygous state, and two in a heterozygous state (Kudi et al. 2006; Bargal et al. 2006; Encarnacao et al. 2009; Cathey et al. 2010; Coutinho et al. 2011; Cury et al. 2013; Aggarwal et al. 2014). The variant has also been found in a heterozygous state in at least 22 healthy individuals (Kudo et al. 2006; Coutinho et al. 2011). Coutinho et al. (2011) demonstrated the high frequency of the variant was due to a founder effect. Plante et al. (2008) identified the variant in 27/27 obligate carriers from the Saguenay-Lac-Saint-Jean region of Quebec, which has the highest carrier rate of mucolipidosis type II in the world at 1/39, and demonstrated that this was also due to a founder effect. The variant was absent from 95 control individuals in the above studies but is reported at a frequency of 0.00085 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the variant does produce a truncated protein that is retained in the ER and not transported to the Golgi, and therefore does not form a mature subunit (De Pace et al. 2014). The p.Leu1168GlnfsTer5 variant has also been shown to result in absent or significantly decreased enzyme activity in patient fibroblasts (Kudo et al. 2006; Encarnacao et al. 2009; Velho et al. 2015). Due to the potential impact of frameshift variants and the collective evidence from the literature, the p.Leu1168GlnfsTer5 variant is classified as pathogenic for GNPTAB-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
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Pathogenic
(Dec 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Pseudo-Hurler polydystrophy
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194241.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_024312.4(GNPTAB):c.3503_3504delTC(L1168Qfs*5) is classified as pathogenic in the context of GNPTAB-related disorders. Sources cited for classification include the following: PMID 24375680, 16465621, 20880125 and 21228398. Classification … (more)
NM_024312.4(GNPTAB):c.3503_3504delTC(L1168Qfs*5) is classified as pathogenic in the context of GNPTAB-related disorders. Sources cited for classification include the following: PMID 24375680, 16465621, 20880125 and 21228398. Classification of NM_024312.4(GNPTAB):c.3503_3504delTC(L1168Qfs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type II
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001424432.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
|
|
|
Pathogenic
(May 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type II
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001737183.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Sex: mixed
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pseudo-Hurler polydystrophy
Mucolipidosis type II
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000824094.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu1168Glnfs*5) in the GNPTAB gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu1168Glnfs*5) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is present in population databases (rs34002892, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with mucolipidosis (PMID: 16465621, 20880125, 24375680, 25606425, 27710913). This variant is also known as 3665_3666delTC, FS1172X. ClinVar contains an entry for this variant (Variation ID: 2771). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199035.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247315.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
GNPTAB: PVS1, PM3:Strong, PM2
Number of individuals with the variant: 9
|
|
|
Pathogenic
(Feb 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281219.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
|
|
|
Pathogenic
(Sep 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type II
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699482.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
Variant summary: The GNPTAB c.3503_3504delTC (p.Leu1168Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent GNPTAB protein due to nonsense … (more)
Variant summary: The GNPTAB c.3503_3504delTC (p.Leu1168Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent GNPTAB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3410T>A/p.Leu1137X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 66/121350 control chromosomes at a frequency of 0.0005439, which does not exceed the estimated maximal expected allele frequency of a pathogenic GNPTAB variant (0.0022361). This variant has been reported in many affected individuals both as homozygotes and compound heterozygotes. Functional studies showed that this variant led to nearly non-detectable level of enzyme activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
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Pathogenic
(Dec 08, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000226964.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 60
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type II
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163704.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
|
|
|
Pathogenic
(Oct 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type II
Affected status: unknown
Allele origin:
unknown
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976909.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PVS1, PM2, PP3, PP5
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type II
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318788.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported … (more)
Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002771, PMID:16465621). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0005511). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Coarse facial features (present)
|
|
|
Pathogenic
(Aug 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type II
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002583503.1
First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022 |
Comment:
A homozygous single base pair deletion in exon 22 of the GNTPAB gene that results in a frameshift and premature truncation of the protein 5 … (more)
A homozygous single base pair deletion in exon 22 of the GNTPAB gene that results in a frameshift and premature truncation of the protein 5 amino acids downstream to codon 1168, (p.Leu1168Glnfs*5 ;ENST00000299314.12) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.001% in our internal database. The in silico prediction of the variant is damaging MutationTaster2. The reference region is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic (less)
Age: 0-9 years
Method: DNA extracted from blood was used to perform targeted gene capture using a custom smMIP panel. The libraries were sequenced to mean >100-300X coverage on the Illumina MiSeq sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37) using the BWA program and analyzed using Picard and GATK version 4.1.2 to identify variants relevant to the clinical indication.
|
|
|
Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: provider interpretation, clinical testing
|
Mucolipidosis type II
Pseudo-Hurler polydystrophy
Affected status: no
Allele origin:
paternal
|
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System
Accession: SCV000804458.2
First in ClinVar: Sep 07, 2018 Last updated: Dec 11, 2022 |
Comment:
This 9 year old male with autism spectrum disorder, intellectual disability, severe irritability, premature adrenarche, and macrocephaly was found to carry a paternally inherited variant … (more)
This 9 year old male with autism spectrum disorder, intellectual disability, severe irritability, premature adrenarche, and macrocephaly was found to carry a paternally inherited variant in GNPTAB. This variant has been reported in association with mucolipidosis II, which is inherited in an autosomal recessive fashion. Because this patient lacks the majority of the features of ML II, clinical correlation is felt to be very poor. His father is also unaffected. This indicates likely carrier status. (less)
Observation 1:
Clinical Features:
Autistic disorder of childhood onset (present) , Intellectual disability (present) , Irritability (present) , Premature adrenarche (present) , Macrocephalus (present)
Age: 0-9 years
Sex: male
Secondary finding: no
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-04-27
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Autistic disorder of childhood onset (present) , Intellectual disability (present) , Irritability (present) , Premature adrenarche (present) , Macrocephalus (present)
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-04-27
Testing laboratory interpretation: Pathogenic
|
|
|
Pathogenic
(Apr 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321745.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25788519, 16465621, 18190596, 21228398, 25606425, 20880125, 24375680, 27710913, 27785713, 28918368, 29289611, 23566849, 16630736, 24685522, 19659762, 25107912, 30209781, 30548430, 29620724, 29704188, 30105123, 22570975, 31038846, 19617216, 31618753, 32651481, 32036093, 34426522, 33594065, 31589614, 33083013, 32981126, 31758855, 33854947) (less)
|
|
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Pathogenic
(Aug 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type II
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807365.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 moderated
Number of individuals with the variant: 1
Clinical Features:
Decreased body weight (present) , Hypoplastic scapulae (present) , Thoracic hypoplasia (present) , Short palpebral fissure (present) , Arachnodactyly (present) , Glossoptosis (present) , Micrognathia … (more)
Decreased body weight (present) , Hypoplastic scapulae (present) , Thoracic hypoplasia (present) , Short palpebral fissure (present) , Arachnodactyly (present) , Glossoptosis (present) , Micrognathia (present) , Short stature (present) , Bowing of the long bones (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(Oct 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024888.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Dec 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741655.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.3503_3504delTC (p.L1168Qfs*5) alteration, located in exon 19 (coding exon 19) of the GNPTAB gene, consists of a deletion of 2 nucleotides from position 3503 … (more)
The c.3503_3504delTC (p.L1168Qfs*5) alteration, located in exon 19 (coding exon 19) of the GNPTAB gene, consists of a deletion of 2 nucleotides from position 3503 to 3504, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this alteration has an overall frequency of 0.05% (139/282744) total alleles studied. The highest observed frequency was 0.08% (23/30614) of South Asian alleles. This common disease-causing alteration (referred to as FS1172X in some publications) is well described in the literature and has been reported in the homozygous and compound heterozygous states in many individuals with GNTAB-related disorders (Alegra, 2014; Coutinho, 2011; Kudo, 2006). Functional studies showed that this alteration results in a loss of GlcNAc-1-phosphotransferase activity (Kudo, 2006; Velho, 2015). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Pseudo-Hurler polydystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005061051.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Comment:
The frameshift variant c.3503_3504del (p.Leu1168GlnfsTer5) in the GNPTAB gene has been reported previously in homozygous state in multiple individuals affected with Mucolipidosis Type II and … (more)
The frameshift variant c.3503_3504del (p.Leu1168GlnfsTer5) in the GNPTAB gene has been reported previously in homozygous state in multiple individuals affected with Mucolipidosis Type II and Type III. It is the most common variant. This variant is reported with the allele frequency (0.04%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic (Multiple submitters). This variant causes a frameshift starting with codon Leucine 1168, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 5 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the skeletal system (present)
|
|
|
Pathogenic
(Jan 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Mucolipidosis type II
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005088803.2
First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024 |
Comment:
This variant has been previously reported as most frequently found pathogenic mutation in individuals affected with mucolipidosis II and III alpha/beta. The variant is located … (more)
This variant has been previously reported as most frequently found pathogenic mutation in individuals affected with mucolipidosis II and III alpha/beta. The variant is located at the region that codes for the β subunit of phosphotransferase, has been associated with the severe phenotype when found in homozygosity or when found in heterozygosity with nonsense mutations or frameshift mutations [PMID: 23566849, 18190596]. (less)
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Pathogenic
(Sep 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mucolipidosis type II
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005374077.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
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pathologic
(May 10, 2012)
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no assertion criteria provided
Method: curation
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Mucolipidosis III Alpha/Beta
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000054684.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2013 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Sep 01, 2011)
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no assertion criteria provided
Method: literature only
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MUCOLIPIDOSIS II ALPHA/BETA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023057.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 19, 2017 |
Comment on evidence:
In 8 of 9 pedigrees with mucolipidosis II (252500) and 5 of 7 with mucolipidosis IIIA (252600), Kudo et al. (2006) identified a frameshift mutation … (more)
In 8 of 9 pedigrees with mucolipidosis II (252500) and 5 of 7 with mucolipidosis IIIA (252600), Kudo et al. (2006) identified a frameshift mutation in the GNPTAB gene consisting of deletion of 2 nucleotides (3665_3666delTC based on numbering of the first base in the initiation codon of a BAC clone) beginning at leu1168 and leading to premature termination at amino acid 1172 (Leu1168fsTer1172). This mutation was the most frequent in their study and was found in both the homozygous and compound heterozygous state, in combination with severe mutations (i.e., mutations preventing the generation of active enzyme) in ML II and with mild mutations (i.e., mutations allowing the generation of active enzyme) in ML IIIA. In 27 parents of 16 deceased French Canadian children with mucolipidosis II alpha/beta, Plante et al. (2008) identified the 2-bp deletion (which they referred to as 3503_3504delTC based on numbering of the first nucleotide of the start codon as +1; rs34002892) in exon 19 of the GNPTAB gene, resulting in a frameshift and premature termination. All parents carried the mutation in the heterozygous state, indicating that the children were likely homozygous. Genealogic data showed 6 founders (3 couples) with a high probability of having introduced the mutation in the population; all originated from France and were married in the Quebec region in the second half of the 17th century. Plante et al. (2008) noted that the carrier rate of mucolipidosis II is estimated to be 1 in 39 in the Saguenay-Lac-Saint-Jean region. Encarnacao et al. (2009) identified GNPTAB mutations in 9 mostly Portuguese patients with ML II. Eight of 9 patients had a nonsense or frameshift mutation, the most common being the 2-bp deletion (3503delTC) that was found in 45% of the mutant alleles. By haplotype analysis of 44 carriers of the 3503delTC mutation from various populations, Coutinho et al. (2011) found that 59 (97%) of 61 mutant chromosomes shared a common haplotype covering 4 of the 5 polymorphic markers analyzed, indicating a strong founder effect. The 2 remaining chromosomes, both from Italian patients, differed by alleles only at 1 marker. A common haplotype encompassing the 3503delTC mutation was shared by individuals of Italian, Arab-Muslim, Turkish, Argentinian, Brazilian, Irish Traveller, Portuguese, and Canadian origin. The mutation was estimated to have occurred about 2,063 years ago, most likely in a peri-Mediterranean region. (less)
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Pathogenic
(Sep 01, 2011)
|
no assertion criteria provided
Method: literature only
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MUCOLIPIDOSIS III ALPHA/BETA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023058.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 19, 2017 |
Comment on evidence:
In 8 of 9 pedigrees with mucolipidosis II (252500) and 5 of 7 with mucolipidosis IIIA (252600), Kudo et al. (2006) identified a frameshift mutation … (more)
In 8 of 9 pedigrees with mucolipidosis II (252500) and 5 of 7 with mucolipidosis IIIA (252600), Kudo et al. (2006) identified a frameshift mutation in the GNPTAB gene consisting of deletion of 2 nucleotides (3665_3666delTC based on numbering of the first base in the initiation codon of a BAC clone) beginning at leu1168 and leading to premature termination at amino acid 1172 (Leu1168fsTer1172). This mutation was the most frequent in their study and was found in both the homozygous and compound heterozygous state, in combination with severe mutations (i.e., mutations preventing the generation of active enzyme) in ML II and with mild mutations (i.e., mutations allowing the generation of active enzyme) in ML IIIA. In 27 parents of 16 deceased French Canadian children with mucolipidosis II alpha/beta, Plante et al. (2008) identified the 2-bp deletion (which they referred to as 3503_3504delTC based on numbering of the first nucleotide of the start codon as +1; rs34002892) in exon 19 of the GNPTAB gene, resulting in a frameshift and premature termination. All parents carried the mutation in the heterozygous state, indicating that the children were likely homozygous. Genealogic data showed 6 founders (3 couples) with a high probability of having introduced the mutation in the population; all originated from France and were married in the Quebec region in the second half of the 17th century. Plante et al. (2008) noted that the carrier rate of mucolipidosis II is estimated to be 1 in 39 in the Saguenay-Lac-Saint-Jean region. Encarnacao et al. (2009) identified GNPTAB mutations in 9 mostly Portuguese patients with ML II. Eight of 9 patients had a nonsense or frameshift mutation, the most common being the 2-bp deletion (3503delTC) that was found in 45% of the mutant alleles. By haplotype analysis of 44 carriers of the 3503delTC mutation from various populations, Coutinho et al. (2011) found that 59 (97%) of 61 mutant chromosomes shared a common haplotype covering 4 of the 5 polymorphic markers analyzed, indicating a strong founder effect. The 2 remaining chromosomes, both from Italian patients, differed by alleles only at 1 marker. A common haplotype encompassing the 3503delTC mutation was shared by individuals of Italian, Arab-Muslim, Turkish, Argentinian, Brazilian, Irish Traveller, Portuguese, and Canadian origin. The mutation was estimated to have occurred about 2,063 years ago, most likely in a peri-Mediterranean region. (less)
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001960005.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Nov 18, 2016)
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no assertion criteria provided
Method: clinical testing
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Mucolipidosis type II
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132213.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
|
Mucolipidosis type II
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001457938.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964064.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Mucolipidosis type II
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000055988.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Comment:
Comment:
The GNPTAB c.3503_3504delTC (p.Leu1168GlnfsTer5) variant results in a frameshift, and is therefore predicted to result in premature termination of the protein. The variant is well described in the literature and is the most common pathogenic variant for for GNPTAB-related disorders in several populations, usually associated with a severe phenotype. Across a selection of the available literature the p.Leu1168GlnfsTer5 variant has been identified in a total of 100 patients with GNPTAB-related disorders, including 51 in a homozygous state, 47 in a compound heterozygous state, and two in a heterozygous state (Kudi et al. 2006; Bargal et al. 2006; Encarnacao et al. 2009; Cathey et al. 2010; Coutinho et al. 2011; Cury et al. 2013; Aggarwal et al. 2014). The variant has also been found in a heterozygous state in at least 22 healthy individuals (Kudo et al. 2006; Coutinho et al. 2011). Coutinho et al. (2011) demonstrated the high frequency of the variant was due to a founder effect. Plante et al. (2008) identified the variant in 27/27 obligate carriers from the Saguenay-Lac-Saint-Jean region of Quebec, which has the highest carrier rate of mucolipidosis type II in the world at 1/39, and demonstrated that this was also due to a founder effect. The variant was absent from 95 control individuals in the above studies but is reported at a frequency of 0.00085 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the variant does produce a truncated protein that is retained in the ER and not transported to the Golgi, and therefore does not form a mature subunit (De Pace et al. 2014). The p.Leu1168GlnfsTer5 variant has also been shown to result in absent or significantly decreased enzyme activity in patient fibroblasts (Kudo et al. 2006; Encarnacao et al. 2009; Velho et al. 2015). Due to the potential impact of frameshift variants and the collective evidence from the literature, the p.Leu1168GlnfsTer5 variant is classified as pathogenic for GNPTAB-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
NM_024312.4(GNPTAB):c.3503_3504delTC(L1168Qfs*5) is classified as pathogenic in the context of GNPTAB-related disorders. Sources cited for classification include the following: PMID 24375680, 16465621, 20880125 and 21228398. Classification of NM_024312.4(GNPTAB):c.3503_3504delTC(L1168Qfs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Comment:
This sequence change creates a premature translational stop signal (p.Leu1168Glnfs*5) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is present in population databases (rs34002892, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with mucolipidosis (PMID: 16465621, 20880125, 24375680, 25606425, 27710913). This variant is also known as 3665_3666delTC, FS1172X. ClinVar contains an entry for this variant (Variation ID: 2771). For these reasons, this variant has been classified as Pathogenic.
Comment:
GNPTAB: PVS1, PM3:Strong, PM2
Comment:
Variant summary: The GNPTAB c.3503_3504delTC (p.Leu1168Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent GNPTAB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3410T>A/p.Leu1137X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 66/121350 control chromosomes at a frequency of 0.0005439, which does not exceed the estimated maximal expected allele frequency of a pathogenic GNPTAB variant (0.0022361). This variant has been reported in many affected individuals both as homozygotes and compound heterozygotes. Functional studies showed that this variant led to nearly non-detectable level of enzyme activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
PVS1, PM2, PP3, PP5
Comment:
Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002771, PMID:16465621). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0005511). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
A homozygous single base pair deletion in exon 22 of the GNTPAB gene that results in a frameshift and premature truncation of the protein 5 amino acids downstream to codon 1168, (p.Leu1168Glnfs*5 ;ENST00000299314.12) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.001% in our internal database. The in silico prediction of the variant is damaging MutationTaster2. The reference region is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic
Comment:
This 9 year old male with autism spectrum disorder, intellectual disability, severe irritability, premature adrenarche, and macrocephaly was found to carry a paternally inherited variant in GNPTAB. This variant has been reported in association with mucolipidosis II, which is inherited in an autosomal recessive fashion. Because this patient lacks the majority of the features of ML II, clinical correlation is felt to be very poor. His father is also unaffected. This indicates likely carrier status.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25788519, 16465621, 18190596, 21228398, 25606425, 20880125, 24375680, 27710913, 27785713, 28918368, 29289611, 23566849, 16630736, 24685522, 19659762, 25107912, 30209781, 30548430, 29620724, 29704188, 30105123, 22570975, 31038846, 19617216, 31618753, 32651481, 32036093, 34426522, 33594065, 31589614, 33083013, 32981126, 31758855, 33854947)
Comment:
ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 moderated
Comment:
The c.3503_3504delTC (p.L1168Qfs*5) alteration, located in exon 19 (coding exon 19) of the GNPTAB gene, consists of a deletion of 2 nucleotides from position 3503 to 3504, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this alteration has an overall frequency of 0.05% (139/282744) total alleles studied. The highest observed frequency was 0.08% (23/30614) of South Asian alleles. This common disease-causing alteration (referred to as FS1172X in some publications) is well described in the literature and has been reported in the homozygous and compound heterozygous states in many individuals with GNTAB-related disorders (Alegra, 2014; Coutinho, 2011; Kudo, 2006). Functional studies showed that this alteration results in a loss of GlcNAc-1-phosphotransferase activity (Kudo, 2006; Velho, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The frameshift variant c.3503_3504del (p.Leu1168GlnfsTer5) in the GNPTAB gene has been reported previously in homozygous state in multiple individuals affected with Mucolipidosis Type II and Type III. It is the most common variant. This variant is reported with the allele frequency (0.04%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic (Multiple submitters). This variant causes a frameshift starting with codon Leucine 1168, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 5 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has been previously reported as most frequently found pathogenic mutation in individuals affected with mucolipidosis II and III alpha/beta. The variant is located at the region that codes for the β subunit of phosphotransferase, has been associated with the severe phenotype when found in homozygosity or when found in heterozygosity with nonsense mutations or frameshift mutations [PMID: 23566849, 18190596].
Comment:
Converted during submission to Pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002583503.1
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Comment:
The p.Leu1168GlnfsX5 mutation is the most common mucolipidosis II alpha/beta mutation worldwide and has also been shown to cause Mucolipidosis IIIA in the compound heterozygous state, in combination with mild mutations (Kudo, 2006, summarized in De Pace 2013). This variant has been identified in 0.06% (5/8254) of European American chromosomes and 0.047% (2/4264) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs34002892), consistent with recessive carrier frequencies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1168 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Mucolipidosis II alpha/beta in an autosomal recessive manner.
Comment:
The GNPTAB c.3503_3504delTC (p.Leu1168GlnfsTer5) variant results in a frameshift, and is therefore predicted to result in premature termination of the protein. The variant is well described in the literature and is the most common pathogenic variant for for GNPTAB-related disorders in several populations, usually associated with a severe phenotype. Across a selection of the available literature the p.Leu1168GlnfsTer5 variant has been identified in a total of 100 patients with GNPTAB-related disorders, including 51 in a homozygous state, 47 in a compound heterozygous state, and two in a heterozygous state (Kudi et al. 2006; Bargal et al. 2006; Encarnacao et al. 2009; Cathey et al. 2010; Coutinho et al. 2011; Cury et al. 2013; Aggarwal et al. 2014). The variant has also been found in a heterozygous state in at least 22 healthy individuals (Kudo et al. 2006; Coutinho et al. 2011). Coutinho et al. (2011) demonstrated the high frequency of the variant was due to a founder effect. Plante et al. (2008) identified the variant in 27/27 obligate carriers from the Saguenay-Lac-Saint-Jean region of Quebec, which has the highest carrier rate of mucolipidosis type II in the world at 1/39, and demonstrated that this was also due to a founder effect. The variant was absent from 95 control individuals in the above studies but is reported at a frequency of 0.00085 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the variant does produce a truncated protein that is retained in the ER and not transported to the Golgi, and therefore does not form a mature subunit (De Pace et al. 2014). The p.Leu1168GlnfsTer5 variant has also been shown to result in absent or significantly decreased enzyme activity in patient fibroblasts (Kudo et al. 2006; Encarnacao et al. 2009; Velho et al. 2015). Due to the potential impact of frameshift variants and the collective evidence from the literature, the p.Leu1168GlnfsTer5 variant is classified as pathogenic for GNPTAB-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
NM_024312.4(GNPTAB):c.3503_3504delTC(L1168Qfs*5) is classified as pathogenic in the context of GNPTAB-related disorders. Sources cited for classification include the following: PMID 24375680, 16465621, 20880125 and 21228398. Classification of NM_024312.4(GNPTAB):c.3503_3504delTC(L1168Qfs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Comment:
This sequence change creates a premature translational stop signal (p.Leu1168Glnfs*5) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). This variant is present in population databases (rs34002892, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with mucolipidosis (PMID: 16465621, 20880125, 24375680, 25606425, 27710913). This variant is also known as 3665_3666delTC, FS1172X. ClinVar contains an entry for this variant (Variation ID: 2771). For these reasons, this variant has been classified as Pathogenic.
Comment:
GNPTAB: PVS1, PM3:Strong, PM2
Comment:
Variant summary: The GNPTAB c.3503_3504delTC (p.Leu1168Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent GNPTAB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3410T>A/p.Leu1137X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 66/121350 control chromosomes at a frequency of 0.0005439, which does not exceed the estimated maximal expected allele frequency of a pathogenic GNPTAB variant (0.0022361). This variant has been reported in many affected individuals both as homozygotes and compound heterozygotes. Functional studies showed that this variant led to nearly non-detectable level of enzyme activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
PVS1, PM2, PP3, PP5
Comment:
Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002771, PMID:16465621). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0005511). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
A homozygous single base pair deletion in exon 22 of the GNTPAB gene that results in a frameshift and premature truncation of the protein 5 amino acids downstream to codon 1168, (p.Leu1168Glnfs*5 ;ENST00000299314.12) was detected. This variant has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.001% in our internal database. The in silico prediction of the variant is damaging MutationTaster2. The reference region is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic
Comment:
This 9 year old male with autism spectrum disorder, intellectual disability, severe irritability, premature adrenarche, and macrocephaly was found to carry a paternally inherited variant in GNPTAB. This variant has been reported in association with mucolipidosis II, which is inherited in an autosomal recessive fashion. Because this patient lacks the majority of the features of ML II, clinical correlation is felt to be very poor. His father is also unaffected. This indicates likely carrier status.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25788519, 16465621, 18190596, 21228398, 25606425, 20880125, 24375680, 27710913, 27785713, 28918368, 29289611, 23566849, 16630736, 24685522, 19659762, 25107912, 30209781, 30548430, 29620724, 29704188, 30105123, 22570975, 31038846, 19617216, 31618753, 32651481, 32036093, 34426522, 33594065, 31589614, 33083013, 32981126, 31758855, 33854947)
Comment:
ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 moderated
Comment:
The c.3503_3504delTC (p.L1168Qfs*5) alteration, located in exon 19 (coding exon 19) of the GNPTAB gene, consists of a deletion of 2 nucleotides from position 3503 to 3504, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this alteration has an overall frequency of 0.05% (139/282744) total alleles studied. The highest observed frequency was 0.08% (23/30614) of South Asian alleles. This common disease-causing alteration (referred to as FS1172X in some publications) is well described in the literature and has been reported in the homozygous and compound heterozygous states in many individuals with GNTAB-related disorders (Alegra, 2014; Coutinho, 2011; Kudo, 2006). Functional studies showed that this alteration results in a loss of GlcNAc-1-phosphotransferase activity (Kudo, 2006; Velho, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The frameshift variant c.3503_3504del (p.Leu1168GlnfsTer5) in the GNPTAB gene has been reported previously in homozygous state in multiple individuals affected with Mucolipidosis Type II and Type III. It is the most common variant. This variant is reported with the allele frequency (0.04%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic (Multiple submitters). This variant causes a frameshift starting with codon Leucine 1168, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 5 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has been previously reported as most frequently found pathogenic mutation in individuals affected with mucolipidosis II and III alpha/beta. The variant is located at the region that codes for the β subunit of phosphotransferase, has been associated with the severe phenotype when found in homozygosity or when found in heterozygosity with nonsense mutations or frameshift mutations [PMID: 23566849, 18190596].
Comment:
Converted during submission to Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| GNPTAB-Related Disorders. | Adam MP | - | 2019 | PMID: 20301728 |
| Solving a case of allelic dropout in the GNPTAB gene: implications in the molecular diagnosis of mucolipidosis type III alpha/beta. | Coutinho MF | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 27710913 |
| Analyses of disease-related GNPTAB mutations define a novel GlcNAc-1-phosphotransferase interaction domain and an alternative site-1 protease cleavage site. | Velho RV | Human molecular genetics | 2015 | PMID: 25788519 |
| Pitfalls in the prenatal diagnosis of mucolipidosis II alpha/beta: A case report. | Alegra T | Meta gene | 2014 | PMID: 25606425 |
| A novel mouse model of a patient mucolipidosis II mutation recapitulates disease pathology. | Paton L | The Journal of biological chemistry | 2014 | PMID: 25107912 |
| Prenatal skeletal dysplasia phenotype in severe MLII alpha/beta with novel GNPTAB mutation. | Aggarwal S | Gene | 2014 | PMID: 24685522 |
| Mucolipidosis II-related mutations inhibit the exit from the endoplasmic reticulum and proteolytic cleavage of GlcNAc-1-phosphotransferase precursor protein (GNPTAB). | De Pace R | Human mutation | 2014 | PMID: 24375680 |
| Mucolipidosis II and III alpha/beta in Brazil: analysis of the GNPTAB gene. | Cury GK | Gene | 2013 | PMID: 23566849 |
| Mucolipidosis III Alpha/Beta – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2012 | PMID: 20301730 |
| Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
| Origin and spread of a common deletion causing mucolipidosis type II: insights from patterns of haplotypic diversity. | Coutinho MF | Clinical genetics | 2011 | PMID: 20880125 |
| Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. | Cathey SS | Journal of medical genetics | 2010 | PMID: 19617216 |
| Molecular analysis of the GNPTAB and GNPTG genes in 13 patients with mucolipidosis type II or type III - identification of eight novel mutations. | Encarnação M | Clinical genetics | 2009 | PMID: 19659762 |
| Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population. | Plante M | Clinical genetics | 2008 | PMID: 18190596 |
| When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients. | Bargal R | Molecular genetics and metabolism | 2006 | PMID: 16630736 |
| Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene. | Kudo M | American journal of human genetics | 2006 | PMID: 16465621 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GNPTAB | - | - | - | - |
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Text-mined citations for rs34002892 ...
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Record last updated Oct 27, 2024
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