ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.604C>T (p.Arg202Cys)

gnomAD frequency: 0.00001  dbSNP: rs749595299
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000596130 SCV000700621 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248872 SCV001422547 uncertain significance Sphingomyelin/cholesterol lipidosis 2020-01-22 criteria provided, single submitter curation The p.Arg202Cys variant in SMPD1 (also known as p.Arg200Cys due to a difference in cDNA numbering) has been reported in at least 1 individual with Niemann-Pick disease (PMID: 12369017), and has been identified in 0.003% (1/29904) of South Asian chromosomes and 0.002% (2/102350) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs749595299). 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: 496912) as a VUS by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg202Cys variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015).
Invitae RCV003767349 SCV004570129 uncertain significance Niemann-Pick disease, type B; Niemann-Pick disease, type A 2022-12-25 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg202 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 34273913), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 496912). This missense change has been observed in individual(s) with Niemann-Pick disease and/or Niemann-Pick disease, type B (PMID: 12369017; Invitae). This variant is present in population databases (rs749595299, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 202 of the SMPD1 protein (p.Arg202Cys).

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