ClinVar Miner

Submissions for variant NM_000262.3(NAGA):c.479C>G (p.Ser160Cys) (rs121434532)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000169668 SCV000221201 likely pathogenic Alpha-N-acetylgalactosaminidase deficiency type 1 2013-11-26 criteria provided, single submitter clinical testing The Ser160Cys variant in NAGA has been previously identified in 1 compound heterozygous individual with Alpha-N-acetylgalactosaminidase (NAGA) deficiency and segregated with enzyme deficiency in a sibling (Keulemans 1996). Functional studies indicate this variant results in 4% residual NAGA activity possibly explaining the milder than typical phenotype, particularly in the clinically unaffected sibling with reduced enzyme activity (Keulemans 1996). In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001092858 SCV001249564 pathogenic not provided 2017-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000169668 SCV001306454 uncertain significance Alpha-N-acetylgalactosaminidase deficiency type 1 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001145759 SCV001306455 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV000169668 SCV001509069 uncertain significance Alpha-N-acetylgalactosaminidase deficiency type 1 2020-08-10 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 160 of the NAGA protein (p.Ser160Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs121434532, ExAC 0.3%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with alpha-NAGA deficiency (PMID: 8782044). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. However, this individual has a sibling with the same genotype who is clinically unaffected (PMID: 8782044, 11313741). ClinVar contains an entry for this variant (Variation ID: 18165). Experimental studies have shown that cells derived from an individual carrying this variant and a second pathogenic variant have reduced alpha-NAGA enzyme activity (PMID: 8071745, 8782044). This missense change results in reduced protein expression, possibly due to protein misfolding (PMID: 8782044, 23045655). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000019795 SCV000040093 pathogenic Schindler disease, type 3 1996-06-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001092858 SCV001740072 likely pathogenic not provided no assertion criteria provided clinical testing

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