ClinVar Genomic variation as it relates to human health
NM_000262.3(NAGA):c.973G>A (p.Glu325Lys)
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.
Pathogenic(11); Likely pathogenic(9); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000262.3(NAGA):c.973G>A (p.Glu325Lys)
Variation ID: 18162 Accession: VCV000018162.55
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.2 22: 42061052 (GRCh38) [ NCBI UCSC ] 22: 42457056 (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 Apr 4, 2013 Jun 2, 2024 Mar 23, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000262.3:c.973G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000253.1:p.Glu325Lys missense NM_001362848.1:c.973G>A NP_001349777.1:p.Glu325Lys missense NM_001362850.1:c.973G>A NP_001349779.1:p.Glu325Lys missense NC_000022.11:g.42061052C>T NC_000022.10:g.42457056C>T NG_009247.1:g.14791G>A P17050:p.Glu325Lys - Protein change
- E325K
- Other names
- -
- Canonical SPDI
- NC_000022.11:42061051:C:T
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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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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
Trans-Omics for Precision Medicine (TOPMed) 0.00223
The Genome Aggregation Database (gnomAD) 0.00225
The Genome Aggregation Database (gnomAD), exomes 0.00247
Exome Aggregation Consortium (ExAC) 0.00252
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
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. |
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NAGA | - | - |
GRCh38 GRCh37 |
207 | 409 |
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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Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Mar 23, 2024 | RCV000019792.44 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2022 | RCV000256069.24 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2022 | RCV000501877.7 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 12, 2021 | RCV000660647.11 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Mar 17, 2024 | RCV001148412.14 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 30, 2023 | RCV001195394.9 | |
See cases
|
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 7, 2019 | RCV002251915.2 |
Pathogenic (1) |
criteria provided, single submitter
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Dec 11, 2020 | RCV004018646.1 |
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. |
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Pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Alpha-N-acetylgalactosaminidase deficiency
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000595898.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
|
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Alpha-N-acetylgalactosaminidase deficiency type 1
Alpha-N-acetylgalactosaminidase deficiency type 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893593.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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Uncertain significance
(May 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Alpha-N-acetylgalactosaminidase deficiency type 1
Affected status: yes
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746490.2
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
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Uncertain significance
(May 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365743.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
The p.Glu325Lys variant in NAGA has been previously reported in 4 individuals with Schindler disease: 3 in the homozygous state from consanguineous families, and one … (more)
The p.Glu325Lys variant in NAGA has been previously reported in 4 individuals with Schindler disease: 3 in the homozygous state from consanguineous families, and one in the compound heterozygous state with another presumably pathogenic NAGA variant and segregated with disease in 1 affected family member (Wang 1990, Keulemans 1996, Bakker 2001, Clark 2009). However two siblings of two affected individuals had the p.Glu325Lys variant (1 homozygote and 1 compound heterozygote) but were clinically unaffected, despite reduced enzyme activity (Wang 1990, Wang 1994, Keulemans 1996, Bakker 2001, Clark 2009). Thus, variable expressivity and reduced penetrance has been suggested to occur in Schindler disease. The p.Glu325Lys variant has also been identified in 0.4% (515/129126) European chromosomes by gnomAD (http://gnomad.broadinstitute.org/), which is significantly higher than the maximum expected allele frequency for a rare disease. Computational prediction tools and conservation analyses suggest this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu325Lys variant is uncertain due to conflicting evidence. ACMG/AMP criteria applied: PM3, PS3_Supporting, BS1, BP4. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Alpha-N-acetylgalactosaminidase deficiency type 2
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001370663.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: NAGA c.973G>A (p.Glu325Lys) results in a conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded … (more)
Variant summary: NAGA c.973G>A (p.Glu325Lys) results in a conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 251354 control chromosomes (gnomAD). c.973G>A has been reported in the literature in multiple individuals affected with alpha-N-Acetylgalactosamidase defiency, primarily with infantile-onset (AKA Schindler disease; examples- Wang_1990, Keulemans_1996, Bakker_2001, Chabas_2007). These data indicate that the variant is very likely to be associated with disease. The variant has also been detected as both homozygous (e.g. Keulemans_1996) and compound heterozygous (e.g. Bakker_2001) in asymptomatic siblings of children with Schindler disease, indicating that this variant may result in a spectrum of clinical presentations. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (examples: Wang_1990, Bakker_2001). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447717.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Microcephaly (present) , Hypotonia (present) , Global developmental delay (present) , Myopathy (present) , Congenital muscular dystrophy (present)
Sex: male
|
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Likely pathogenic
(Mar 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Schindler disease, type i
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448884.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the nervous system (present) , Ear malformation (present) , EEG abnormality (present) , Chorea (present) , Head tremor (present) , Reduced visual acuity … (more)
Abnormality of the nervous system (present) , Ear malformation (present) , EEG abnormality (present) , Chorea (present) , Head tremor (present) , Reduced visual acuity (present) , Feeding difficulties (present) , Constipation (present) , Sleep disturbance (present) , Global developmental delay (present) , Muscular hypotonia (present) , Oculogyric crisis (present) , Developmental regression (present) , Abnormality of the foot (present) , Bruxism (present) , Abnormality of brain morphology (present) (less)
Sex: female
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Likely pathogenic
(Aug 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Alpha-N-acetylgalactosaminidase deficiency type 1
Alpha-N-acetylgalactosaminidase deficiency type 2
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061521.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PP3, PM3
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Likely pathogenic
(Oct 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Alpha-N-acetylgalactosaminidase deficiency type 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556529.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
The NAGA c.973G>A variant is classified as Likely Pathogenic (PS3, PM3_S, PP3, PP5) This variant is a single nucleotide change from a guanine to an … (more)
The NAGA c.973G>A variant is classified as Likely Pathogenic (PS3, PM3_S, PP3, PP5) This variant is a single nucleotide change from a guanine to an adenine at position 973 which is predicted to change the glutamic acid at position 325 in the protein to lysine. The variant has been reported in both the homozygous and compound heterozygous states in multiple individuals affected with alpha-NAGA deficiency, with variable expressivity and reduced penetrance (PMID: 2243144, 8782044, 1313741) (PM3_S). Functional studies demostrated that this variant results significantly reduced in the alpha-NAGA enzyme activity (PMID: 2243144, 8040340, 14685826) (PS3). The variant is in dbSNP (rs121434529) and has been reported in population databases (gnomAD (v3.1.2) 331/152198, 0 homozygote). The variant has been reported in ClinVar (ID: 18162) and HGMD (Accession: CM900169) as a disease causing variant (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Alpha-N-acetylgalactosaminidase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769082.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-N-acetylgalactosaminidase deficiency (MONDO#0017779). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The clinical heterogeneity among individuals with alpha-N-acetylgalactosaminidase ranges from 'non-disease' to infantile neuroaxonal dystrophy (PMID:11313741). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (696 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated alpha galactosidase A C-terminal beta sandwich domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many individuals with alpha-N-acetylgalactosaminidase (NAGA) deficiency and with variable clinical presentation (ClinVar, PMIDs: 11313741, 17171432). PMID:11313741 reported this variant as homozygous in a 3-year old proband with congenital cataract, slight motor retardation and secondary demyelinisation, and his 7-year old healthy sibling; both siblings had undetectable/profound deficiency in NAGA activity. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Profound NAGA enzyme deficiency has been reported in tissue samples from individuals who are homozygous or compound heterozygous with this variant (PMIDs: 11313741, 17171432). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Dec 06, 2021)
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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: SCV000321922.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Functional studies indicate this variant results in loss of alpha-N-acetylgalactosaminidase activity (Wang et al., 1990); This variant is associated with the following publications: (PMID: 17171432, … (more)
Functional studies indicate this variant results in loss of alpha-N-acetylgalactosaminidase activity (Wang et al., 1990); This variant is associated with the following publications: (PMID: 17171432, 19683538, 29373990, 30487145, 8040340, 14685826, 8782044, 2243144, 11313741, 27138754, 29431110, 31980526, 31589614, 32860008) (less)
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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518355.3
First in ClinVar: May 28, 2022 Last updated: Apr 01, 2023 |
|
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Likely pathogenic
(Mar 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Alpha-N-acetylgalactosaminidase deficiency type 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807878.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
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Likely pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
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Alpha-N-acetylgalactosaminidase deficiency type 2
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804742.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
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Likely pathogenic
(Aug 01, 2022)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004153179.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
NAGA: PP1:Strong, PS3:Moderate, PM2:Supporting, PM3:Supporting
Number of individuals with the variant: 1
|
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Pathogenic
(Aug 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331365.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
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Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Alpha-N-acetylgalactosaminidase deficiency type 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001309305.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Alpha-N-acetylgalactosaminidase deficiency type 1
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426613.1
First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020 |
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Likely pathogenic
(Jul 07, 2019)
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criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523202.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS3, PM3, PP1, PP2, PP3
Clinical Features:
Polyhydramnios (present) , Neurodevelopmental abnormality (present) , Large for gestational age (present) , Generalized hypertrichosis (present) , Dysplastic corpus callosum (present) , Coarse facial features … (more)
Polyhydramnios (present) , Neurodevelopmental abnormality (present) , Large for gestational age (present) , Generalized hypertrichosis (present) , Dysplastic corpus callosum (present) , Coarse facial features (present) , Autistic behavior (present) , Abnormal cardiac septum morphology (present) (less)
Geographic origin: Brazil
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Likely pathogenic
(Dec 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017886.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Alpha-N-acetylgalactosaminidase deficiency type 1
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000825839.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 325 of the NAGA protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 325 of the NAGA protein (p.Glu325Lys). This variant is present in population databases (rs121434529, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency (PMID: 1131374, 7707696, 8040340, 8071745). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18162). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NAGA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NAGA function (PMID: 2243144, 8782044, 11313741). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 11, 2020)
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criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004961145.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.973G>A (p.E325K) alteration is located in exon 8 (coding exon 8) of the NAGA gene. This alteration results from a G to A substitution … (more)
The c.973G>A (p.E325K) alteration is located in exon 8 (coding exon 8) of the NAGA gene. This alteration results from a G to A substitution at nucleotide position 973, causing the glutamic acid (E) at amino acid position 325 to be replaced by a lysine (K). This mutation was identified in the homozygous state in multiple individuals with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency and has been shown to segregate with disease (van Diggelen, 1987; Bakker, 2001). In one family, a sibling was clinically unaffected with negligible enzymatic activity, suggesting variable expressivity (Bakker, 2001). The p.E325K alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Apr 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713912.4
First in ClinVar: Jun 15, 2021 Last updated: Jun 02, 2024 |
Number of individuals with the variant: 5
|
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Pathogenic
(Feb 01, 2001)
|
no assertion criteria provided
Method: literature only
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SCHINDLER DISEASE, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000040090.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In the 2 German boys first described with Schindler disease (609241) (van Diggelen et al., 1987, 1988), Wang et al. (1990) identified a homozygous 973G-A … (more)
In the 2 German boys first described with Schindler disease (609241) (van Diggelen et al., 1987, 1988), Wang et al. (1990) identified a homozygous 973G-A transition in exon 8 of the NAGA gene, resulting in a glu325-to-lys (E325K) substitution. Keulemans et al. (1996) identified a distant affected relative of the 2 boys who had the E325K homozygous mutation. The boys had approximately 1% residual NAGA activity. Bakker et al. (2001) reported homozygosity for the E325K mutation in a 3-year-old Moroccan boy with alpha-NAGA deficiency. He was born of consanguineous parents. The proband and his 7-year-old healthy brother had undetectable alpha-NAGA activity in leukocytes and a profound deficiency in fibroblasts. The parents had alpha-NAGA activity consistent with heterozygosity. Mutation analysis revealed homozygosity for the E325K mutation in the proband and his healthy brother, whereas a third sib and both parents were heterozygous. The family demonstrated the extreme clinical heterogeneity of alpha-NAGA deficiency, as the homozygous brother at the age of 7 years showed no clinical or neurologic symptoms. (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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Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
High-frequency actionable pathogenic exome variants in an average-risk cohort. | Rego S | Cold Spring Harbor molecular case studies | 2018 | PMID: 30487145 |
The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants. | Reuter MS | CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne | 2018 | PMID: 29431110 |
Exploration of Structural and Functional Variations Owing to Point Mutations in α-NAGA. | Meshach Paul D | Interdisciplinary sciences, computational life sciences | 2018 | PMID: 27138754 |
The 1.9 a structure of human alpha-N-acetylgalactosaminidase: The molecular basis of Schindler and Kanzaki diseases. | Clark NE | Journal of molecular biology | 2009 | PMID: 19683538 |
A new infantile case of alpha-N-acetylgalactosaminidase deficiency. Cardiomyopathy as a presenting symptom. | Chabás A | Journal of inherited metabolic disease | 2007 | PMID: 17171432 |
Structural and immunocytochemical studies on alpha-N-acetylgalactosaminidase deficiency (Schindler/Kanzaki disease). | Sakuraba H | Journal of human genetics | 2004 | PMID: 14685826 |
Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: no association with neuroaxonal dystrophy? | Bakker HD | European journal of human genetics : EJHG | 2001 | PMID: 11313741 |
A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Ménière's syndrome and without mental retardation. | Kodama K | The British journal of dermatology | 2001 | PMID: 11251574 |
Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype. | Keulemans JL | Journal of medical genetics | 1996 | PMID: 8782044 |
alpha-N-acetylgalactosaminidase deficiency with mild clinical manifestations and difficult biochemical diagnosis. | de Jong J | The Journal of pediatrics | 1994 | PMID: 8071745 |
The molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma corporis diffusum with glycopeptiduria. | Wang AM | The Journal of clinical investigation | 1994 | PMID: 8040340 |
Mild phenotypic expression of alpha-N-acetylgalactosaminidase deficiency in two adult siblings. | Chabás A | Journal of inherited metabolic disease | 1994 | PMID: 7707696 |
Cytogenetic analysis of 124 prospectively ascertained male germ cell tumors. | Rodriguez E | Cancer research | 1992 | PMID: 1313741 |
Schindler disease: the molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes an infantile neuroaxonal dystrophy. | Wang AM | The Journal of clinical investigation | 1990 | PMID: 2243144 |
Lysosomal alpha-N-acetylgalactosaminidase deficiency: a new inherited metabolic disease. | van Diggelen OP | Lancet (London, England) | 1987 | PMID: 2889023 |
An interaction model of a Poisson and a renewal process related to neuron firing. | Pooi AH | Biological cybernetics | 1975 | PMID: 1131374 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NAGA | - | - | - | - |
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Text-mined citations for rs121434529 ...
HelpRecord last updated Jun 02, 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.