Submissions for variant NM_000543.5(SMPD1):c.1804C>T (p.Arg602Cys)

gnomAD frequency: 0.00001  dbSNP: rs763099671

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001104540	SCV001261414	uncertain significance	Niemann-Pick disease, type A	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.
Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital	RCV001281431	SCV001468736	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2020-12-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001281431	SCV002294694	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 602 of the SMPD1 protein (p.Arg602Cys). This variant is present in population databases (rs763099671, gnomAD 0.003%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 878168). 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%. This variant disrupts the p.Arg602 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12712061, 15241805, 16010684, 21098024, 27338287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.