ClinVar Genomic variation as it relates to human health
NM_001127178.3(PIGG):c.2624_2625del (p.Gly874_Leu875insTer)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001127178.3(PIGG):c.2624_2625del (p.Gly874_Leu875insTer)
Variation ID: 646604 Accession: VCV000646604.16
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 4p16.3 4: 533870-533871 (GRCh38) [ NCBI UCSC ] 4: 527659-527660 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 14, 2019 Feb 20, 2024 Nov 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001127178.3:c.2624_2625del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001120650.1:p.Gly874_Leu875insTer nonsense NM_001127178.3:c.2624_2625delTA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001127178.2:c.2624_2625delTA NM_001289051.2:c.2357_2358del NP_001275980.1:p.Gly785_Leu786insTer nonsense NM_001289052.2:c.2225_2226del NP_001275981.1:p.Gly741_Leu742insTer nonsense NM_001345986.2:c.2357_2358del NP_001332915.1:p.Gly785_Leu786insTer nonsense NM_001345987.2:c.2333_2334del NP_001332916.1:p.Gly777_Leu778insTer nonsense NM_001345988.2:c.1595_1596del NP_001332917.1:p.Gly531_Leu532insTer nonsense NM_001345990.2:c.1091_1092del NP_001332919.1:p.Gly363_Leu364insTer nonsense NM_001345991.2:c.1091_1092del NP_001332920.1:p.Gly363_Leu364insTer nonsense NM_001345994.2:c.1526_1527del NP_001332923.1:p.Gly508_Leu509insTer nonsense NM_017733.5:c.2600_2601del NP_060203.3:p.Gly866_Leu867insTer nonsense NR_110293.2:n.2704_2705del non-coding transcript variant NR_144326.2:n.2986_2987del non-coding transcript variant NR_144327.2:n.3007_3008del non-coding transcript variant NR_144328.2:n.3173_3174del non-coding transcript variant NR_144329.2:n.2678_2679del non-coding transcript variant NR_144330.2:n.2440_2441del non-coding transcript variant NR_144331.2:n.2676_2677del non-coding transcript variant NR_144332.2:n.2295_2296del non-coding transcript variant NR_144333.2:n.1985_1986del non-coding transcript variant NR_144334.2:n.2175_2176del non-coding transcript variant NC_000004.12:g.533870_533871del NC_000004.11:g.527659_527660del NG_051621.1:g.39671_39672del - Protein change
- Other names
- p.Leu875Ter
- Canonical SPDI
- NC_000004.12:533869:TA:
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00014
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 | ||
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HI score
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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. |
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PIGG | - | - |
GRCh38 GRCh37 |
979 | 1149 |
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. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 20, 2023 | RCV000800923.7 | |
Pathogenic (3) |
criteria provided, single submitter
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Apr 10, 2023 | RCV001008717.7 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 30, 2022 | RCV002249514.2 |
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. |
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Pathogenic
(Apr 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001168498.2
First in ClinVar: Mar 16, 2020 Last updated: Apr 23, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on PIGG expression, resulting in a null enzymatic activity (Tremblay-Laganire C et al., 2021); Nonsense variant predicted to … (more)
Published functional studies demonstrate a damaging effect on PIGG expression, resulting in a null enzymatic activity (Tremblay-Laganire C et al., 2021); Nonsense 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: 28771251, 34113002, 34535746, 34908758, 26996948, 28581210) (less)
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Pathogenic
(Sep 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 53
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV004035164.1
First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Comment:
A homozygous 2 base pair deletion in exon 12 of the PIGG gene that results in premature truncation. This variant has not been reported in … (more)
A homozygous 2 base pair deletion in exon 12 of the PIGG gene that results in premature truncation. This variant has not been reported in 1000 genomes and has a MAF of 0.002%, 0.01% and 0.001% in the gnomAD v3.1, gnomAD v2 and topmed databases respectively. This variant has previously been reported in patients affected with neurodevelopmental disorder with/without hypotonia, seizures, cerebellar atrophy (PMID:28771251). The in-silico prediction is damaging by MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Short stature (present)
Age: 0-9 years
Sex: female
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal recessive 53
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000940667.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu875*) in the PIGG gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu875*) in the PIGG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIGG are known to be pathogenic (PMID: 26996948, 28581210, 28771251). This variant is present in population databases (rs771819481, gnomAD 0.08%). This premature translational stop signal has been observed in individual(s) with autosomal recessive syndromic intellectual disability (PMID: 28771251). This variant is also known as NM_017733.3:c.2600_2601delTA (p.Leu867*). ClinVar contains an entry for this variant (Variation ID: 646604). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001806860.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741098.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(Apr 30, 2022)
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no assertion criteria provided
Method: literature only
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EMM-NULL PHENOTYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002520371.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
Comment on evidence:
Emm-Null Phenotype In 2 adult brothers (one was proband 1) of Indian descent with the Emm- blood group phenotype and naturally occurring anti-Emm antibodies (see … (more)
Emm-Null Phenotype In 2 adult brothers (one was proband 1) of Indian descent with the Emm- blood group phenotype and naturally occurring anti-Emm antibodies (see 619812), Lane et al. (2021) identified a homozygous 2-bp deletion (c.2624_2625delTA, NM_001127178.3) in exon 12 of the PIGG gene, resulting in a frameshift and premature termination (Leu875Ter). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. The mutation was found twice in the gnomAD database (2 of 143,344 alleles, frequency of 1.4 x 10(-5)). It was also found in 2 of 3,052 alleles from South Asian individuals (frequency of 6.6 x 10(-4)). Neither patient had been transfused, and both had naturally occurring anti-Em antibodies. This family and the same 2-bp deletion mutation were also reported by Shah et al. (2021). Neurodevelopmental Disorder with or without Hypotonia, Seizures, and Cerebellar Atrophy In 4 patients, including a sib pair, from 3 unrelated consanguineous families (families 8, 9 and 10) with neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy (NEDHSCA; 616917), Tremblay-Laganiere et al. (2021) identified homozygosity for the c.2624_2625delTA mutation in the PIGG gene. The mutation was reported in the gnomAD database with a minor allele frequency of 0.0000954 in the total population and 0.000784 in the South Asian population. Transfection of PIGG cDNA with the c.2624_2625delTA mutation into PIGO/PIGG double-knockout HEK293 cells showed that the mutation resulted in null enzyme activity. (less)
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Pathogenic
(Jan 20, 2023)
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no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPOTONIA, SEIZURES, AND CEREBELLAR ATROPHY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV003841066.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment on evidence:
Emm-Null Phenotype In 2 adult brothers (one was proband 1) of Indian descent with the Emm- blood group phenotype and naturally occurring anti-Emm antibodies (see … (more)
Emm-Null Phenotype In 2 adult brothers (one was proband 1) of Indian descent with the Emm- blood group phenotype and naturally occurring anti-Emm antibodies (see 619812), Lane et al. (2021) identified a homozygous 2-bp deletion (c.2624_2625delTA, NM_001127178.3) in exon 12 of the PIGG gene, resulting in a frameshift and premature termination (Leu875Ter). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. The mutation was found twice in the gnomAD database (2 of 143,344 alleles, frequency of 1.4 x 10(-5)). It was also found in 2 of 3,052 alleles from South Asian individuals (frequency of 6.6 x 10(-4)). Neither patient had been transfused, and both had naturally occurring anti-Em antibodies. This family and the same 2-bp deletion mutation were also reported by Shah et al. (2021). Neurodevelopmental Disorder with or without Hypotonia, Seizures, and Cerebellar Atrophy In 4 patients, including a sib pair, from 3 unrelated consanguineous families (families 8, 9 and 10) with neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy (NEDHSCA; 616917), Tremblay-Laganiere et al. (2021) identified homozygosity for the c.2624_2625delTA mutation in the PIGG gene. The mutation was reported in the gnomAD database with a minor allele frequency of 0.0000954 in the total population and 0.000784 in the South Asian population. Transfection of PIGG cDNA with the c.2624_2625delTA mutation into PIGO/PIGG double-knockout HEK293 cells showed that the mutation resulted in null enzyme activity. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Anti-Emm, a rare specificity to the high-incidence antigen Emm in an Indian patient defining the new blood group system EMM (ISBT042). | Shah RJ | Asian journal of transfusion science | 2021 | PMID: 34908758 |
PIGG defines the Emm blood group system. | Lane WJ | Scientific reports | 2021 | PMID: 34535746 |
PIGG variant pathogenicity assessment reveals characteristic features within 19 families. | Tremblay-Laganière C | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34113002 |
Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. | Lionel AC | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28771251 |
Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function. | Zhao JJ | Human mutation | 2017 | PMID: 28581210 |
Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia. | Makrythanasis P | American journal of human genetics | 2016 | PMID: 26996948 |
Text-mined citations for rs771819481 ...
HelpRecord last updated Mar 05, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.