ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1177T>G (p.Trp393Gly)

dbSNP: rs120074125
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410490 SCV000486826 pathogenic Niemann-Pick disease, type A 2016-08-17 criteria provided, single submitter clinical testing
Invitae RCV000797253 SCV000936802 pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2023-11-13 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 393 of the SMPD1 protein (p.Trp393Gly). This variant is present in population databases (rs120074125, gnomAD 0.0009%). This missense change has been observed in individuals with Niemann-Pick disease (PMID: 7762557, 17360762). It has also been observed to segregate with disease in related individuals. This variant is also known as W391G. ClinVar contains an entry for this variant (Variation ID: 2991). 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 expected to disrupt SMPD1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 7762557). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248981 SCV001422823 pathogenic Sphingomyelin/cholesterol lipidosis 2020-01-22 criteria provided, single submitter curation The p.Trp393Gly variant in SMPD1 (also known as p.Trp391Gly due to a difference in cDNA numbering) has been reported in at least 25 individuals with Niemann-Pick disease, segregated with disease in 11 affected relatives from 3 families (PMID: 7762557, 17360762), and has been identified in 0.0002% (1/113046) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs120074125). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 2991) as pathogenic by Counsyl and OMIM. In vitro functional studies provide some evidence that the p.Trp393Gly variant may impact protein function (PMID: 7762557). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in at least 25 affected homozygotes increases the likelihood that the p.Trp393Gly variant is pathogenic (PMID: 7762557, 17360762). The phenotype of individuals homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 7762557). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on its presence in related and unrelated affected homozygotes, functional studies, and the phenotype of individuals with the variant being highly specific for disease. ACMG/AMP Criteria applied: PP1_strong, PS3, PM2, PM3, PP3, PP4 (Richards 2015).
Baylor Genetics RCV000410490 SCV004203203 pathogenic Niemann-Pick disease, type A 2023-10-24 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV004546410 SCV005042359 pathogenic not provided 2024-04-01 criteria provided, single submitter clinical testing SMPD1: PP1:Strong, PM2, PM3, PM5, PP4:Moderate, PS3:Moderate, PP3
OMIM RCV000003125 SCV000023283 pathogenic Niemann-pick disease, intermediate, protracted neurovisceral 1995-06-01 no assertion criteria provided literature only
Natera, Inc. RCV000410490 SCV002092263 pathogenic Niemann-Pick disease, type A 2017-03-17 no assertion criteria provided clinical testing

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