Submissions for variant NM_000543.5(SMPD1):c.688C>T (p.Arg230Cys)

gnomAD frequency: 0.00001  dbSNP: rs989639224

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409293	SCV000485757	likely pathogenic	Niemann-Pick disease, type A	2016-02-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229670	SCV001402124	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-10-29	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 230 of the SMPD1 protein (p.Arg230Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with acid sphingomyelinase (ASM) deficiency (PMID: 17011332, 19405096, 22818240, 27338287). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg228Cys. ClinVar contains an entry for this variant (Variation ID: 370432). 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%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 19405096). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248876	SCV001422551	pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Arg230Cys variant in SMPD1 (also known as p.Arg228Cys due to a difference in cDNA numbering) has been reported in at least 7 individuals with Niemann-Pick disease (PMID: 17011332, 22818240, 23356216, 23356216, 23252888, 19405096) and has been identified in 0.001% (1/111638) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs989639224). 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: 370432) as likely pathogenic by Counsyl. In vitro functional studies provide some evidence that the p.Arg230Cys variant may impact protein function (PMID: 19405096). However, these types of assays may not accurately represent biological function. 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 4 affected homozygotes increases the likelihood that the p.Arg230Cys variant is pathogenic (PMID: 17011332, 22818240, 23356216, 19405096). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 23252888, 22818240, 19405096, 23356216). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on in vitro studies and low prevalence in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001229670	SCV001622390	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2021-01-08	criteria provided, single submitter	clinical testing	A homozygous missense variant in exon 2 of the SMPD1 gene that results in the amino acid substitution of Cysteine for Arginine at codon 230 was detected. The observed variant c.688C>T (p.Arg230Cys) has not been reported in the 1000 genomes and gnomAD databases. The variant is reported in ClinVar as a pathogenic variant (ID 357985). The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV002223835	SCV002502706	likely pathogenic	not provided	2020-06-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409293	SCV004203233	pathogenic	Niemann-Pick disease, type A	2023-06-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000409293	SCV002091690	pathogenic	Niemann-Pick disease, type A	2017-08-19	no assertion criteria provided	clinical testing