Submissions for variant NM_000543.5(SMPD1):c.1492C>T (p.Arg498Cys)

gnomAD frequency: 0.00002  dbSNP: rs769904764

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179329	SCV000231561	likely pathogenic	not provided	2014-06-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000674497	SCV000799843	likely pathogenic	Niemann-Pick disease, type A	2018-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700960	SCV000829739	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-10-16	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 498 of the SMPD1 protein (p.Arg498Cys). This variant is present in population databases (rs769904764, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Niemann-Pick disease (PMID: 12369017, 23356216; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198095). 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.Arg498 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1391960, 1885770, 2023926, 18815062). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248982	SCV001422824	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Arg498Cys variant in SMPD1 (also known as p.Arg496Cys due to a difference in cDNA numbering) has been reported in at least 3 individuals with Niemann-Pick disease (PMID: 17011332, 25834946, 23356216) and has been identified in 0.003% (1/30612) of South Asian chromosomes and 0.002% (3/128792) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs769904764). 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: 198095) as likely pathogenic by EGL Genetic Diagnostics, Counsyl, and Invitae. 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 combination with reported pathogenic variants in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Arg498Cys variant is pathogenic (VariationID: 198095, 25834946; PMID: 17011332, 25834946). The phenotype of an individual homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 23356216). Multiple variants in the same region as p.Arg498Cys have been reported in association with disease in ClinVar and the literature and the variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a hot spot and functional domain and supports pathogenicity (VariationID: 2991, 198095; PMID: 18815062, 27725636; DOI: 10.1111/febs.13655). Two additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg498Leu and p.Arg498His, have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 2980, 167712; PMID: 29995201, 18815062, 15221801, 27338287, 26499107, 27725636). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM1, PM3, PP3, PP4 (Richards 2015).
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV000674497	SCV001738433	likely pathogenic	Niemann-Pick disease, type A	2021-04-25	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000179329	SCV002023606	likely pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000674497	SCV004203221	pathogenic	Niemann-Pick disease, type A	2024-03-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003955080	SCV004769358	likely pathogenic	SMPD1-related disorder	2024-09-23	no assertion criteria provided	clinical testing	The SMPD1 c.1492C>T variant is predicted to result in the amino acid substitution p.Arg498Cys. This variant has been reported in individuals with Niemann-Pick disease (reported as R496L in Simonaro et al. 2002. PubMed ID: 12369017; Zhang et al. 2013. PubMed ID: 23356216; Hu et al. 2021. PubMed ID: 33675270). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.