Submissions for variant NM_000543.5(SMPD1):c.631T>C (p.Trp211Arg)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003062323	SCV003439783	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 211 of the SMPD1 protein (p.Trp211Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with acid sphingomyelinase deficiency (PMID: 20386867; Invitae). ClinVar contains an entry for this variant (Variation ID: 2136982). 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. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 20386867). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003138464	SCV003807083	likely pathogenic	Niemann-Pick disease, type A	2022-05-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP3 supporting, PP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004765637	SCV005381792	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2024-08-26	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.631T>C (p.Trp211Arg) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type domain (IPR004843) and Acid sphingomyelinase/endopolyphosphatase, metallophosphatase domain (IPR041805) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242950 control chromosomes. c.631T>C has been reported in the literature in at least one homozygous individual affected with type A Niemann-Pick Disease (e.g., Desnick_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in less than 0.5% of wild-type activity (Desnick_2010). The following publication was ascertained in the context of this evaluation (PMID: 20386867). ClinVar contains an entry for this variant (Variation ID: 2136982). Based on the evidence outlined above, the variant was classified as likely pathogenic.