Submissions for variant NM_000543.5(SMPD1):c.682T>C (p.Cys228Arg)

dbSNP: rs1564923612

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778332	SCV000914526	uncertain significance	Niemann-Pick disease, type A	2018-11-16	criteria provided, single submitter	clinical testing	The SMPD1 c.682T>C (p.Cys228Arg) missene variant has been reported in a compound heterozygous state with a frameshift variant in one individual with severe acid sphyingomyelinase deficiency (Irun et al. 2013). This variant is not reported in the 1000 Genomes Project, Exome Sequencing Project, Exome Aggregation Consortium, or Genome Aggregation Database in a region of good sequencing coverage. It is therefore presumed to be rare. Functional studies of this variant have not been conducted, but it affects a disulfide bond, which may lead to protein misfolding or reduced protein stability. The evidence for this variant is limited. Based on the limited evidence, the p.Cys228Arg variant is classified as of uncertain significance but suspicious for pathogenicity for SMPD1-Related Disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000778332	SCV004205513	likely pathogenic	Niemann-Pick disease, type A	2024-02-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003768424	SCV004569736	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 228 of the SMPD1 protein (p.Cys228Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 23252888). ClinVar contains an entry for this variant (Variation ID: 631662). 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. This variant disrupts the p.Cys228 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 35883096), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.