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
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	2024-02-17	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005236604	SCV005886460	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2025-02-14	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1804C>T (p.Arg602Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249578 control chromosomes. c.1804C>T has been reported in the presumed compound heterozygous state in the literature in at least 1 individual affected with Niemann-Pick Disease (example, Hu_2021). At least 2 different variants affecting the same codon are pathogenic (p.Arg602Pro, p.Arg602His), supporting the critical relevance of codon 602 to SMPD1 protein function (PMID: 21098024, 16010684, 12369017, 15241805, ClinVar). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 878168). Based on the evidence outlined above, the variant was classified as likely pathogenic.