ClinVar Miner

Submissions for variant NM_000262.3(NAGA):c.973G>A (p.Glu325Lys) (rs121434529)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256069 SCV000321922 pathogenic not provided 2021-05-27 criteria provided, single submitter clinical testing Functional studies indicate this variant results in loss of alpha-N-acetylgalactosaminidase activity (Wang et al., 1990); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17171432, 19683538, 29373990, 30487145, 8040340, 14685826, 8782044, 2243144, 11313741, 27138754, 29431110, 31980526, 31589614)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000256069 SCV000331365 pathogenic not provided 2016-08-16 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000501877 SCV000595898 pathogenic Alpha-N-acetylgalactosaminidase deficiency 2016-03-25 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000019792 SCV000746490 uncertain significance Alpha-N-acetylgalactosaminidase deficiency type 1 2020-05-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000660647 SCV000782773 pathogenic Alpha-N-acetylgalactosaminidase deficiency type 2; Alpha-N-acetylgalactosaminidase deficiency type 1 2018-02-16 criteria provided, single submitter clinical testing
Invitae RCV000019792 SCV000825839 pathogenic Alpha-N-acetylgalactosaminidase deficiency type 1 2020-10-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 325 of the NAGA protein (p.Glu325Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121434529, ExAC 0.4%). This variant has been reported segregate with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency in multiple families (PMID: 1131374, 8040340, 7707696, 8071745). Importantly, the clinical presentation associated with alpha-NAGA deficiency varies considerably from asymptomatic to severe infantile neuroaxonal dystrophy (Schindler disease). Multiple experimental studies have demonstrated that this missense change results in nearly complete loss of alpha-NAGA enzyme activity (PMID: 2243144, 8782044, 11313741). In summary, this missense variant has been demonstrated to segregate with alpha-NAGA deficiency. For this reason, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000660647 SCV000893593 likely pathogenic Alpha-N-acetylgalactosaminidase deficiency type 2; Alpha-N-acetylgalactosaminidase deficiency type 1 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001148412 SCV001309305 uncertain significance Alpha-N-acetylgalactosaminidase deficiency type 2 2017-04-27 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195394 SCV001365743 uncertain significance not specified 2019-05-30 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001148412 SCV001370663 pathogenic Alpha-N-acetylgalactosaminidase deficiency type 2 2020-05-11 criteria provided, single submitter clinical testing 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.
Centogene AG - the Rare Disease Company RCV000019792 SCV001426613 pathogenic Alpha-N-acetylgalactosaminidase deficiency type 1 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000256069 SCV001447717 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000019792 SCV001448884 likely pathogenic Alpha-N-acetylgalactosaminidase deficiency type 1 2018-03-07 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000256069 SCV001713912 pathogenic not provided 2019-12-11 criteria provided, single submitter clinical testing
OMIM RCV000019792 SCV000040090 pathogenic Alpha-N-acetylgalactosaminidase deficiency type 1 2001-02-01 no assertion criteria provided literature only

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