ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1280A>G (p.His427Arg)

gnomAD frequency: 0.00001  dbSNP: rs794727629
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000689782 SCV000817449 pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 427 of the SMPD1 protein (p.His427Arg). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with Nieman Pick disease type B (PMID: 20386867). ClinVar contains an entry for this variant (Variation ID: 569207). 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. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 20386867, 25144372). This variant disrupts the p.His427 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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.
Illumina Laboratory Services, Illumina RCV000778333 SCV000914527 uncertain significance Niemann-Pick disease, type A 2018-10-29 criteria provided, single submitter clinical testing The SMPD1 c.1280A>G (p.His427Arg) missense variant has been reported in one study, in which it is found in a compound heterozygous state with another missense variant in one individual with acid sphingomyelinase deficiency (also known as Niemann-Pick disease) (Desnick et al. 2010). Control data are unavailable for the p.His427Arg variant which is reported at a frequency of 0.000018 in the European (non-Finnish) population of the Genome Aggregation Database though this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Functional studies by Desnick et al. (2010) demonstrated that the acid sphingomyelinase activity was less than one percent in 293-T cells expressing the p.His427Arg variant when compared to wild type expressing cells. Based on the limited evidence, the p.His427Arg variant is classified as a variant of unknown 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 RCV000778333 SCV001163305 likely pathogenic Niemann-Pick disease, type A criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230573 SCV003929058 likely pathogenic Sphingomyelin/cholesterol lipidosis 2023-04-24 criteria provided, single submitter clinical testing Variant summary: SMPD1 c.1280A>G (p.His427Arg) results in a non-conservative amino acid change located in the ApaH type calcineurin-like phosphoesterase domain (IPR004843) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249056 control chromosomes (gnomAD). c.1280A>G has been reported in the literature in the compound heterozygous state in an individual affected with Niemann-Pick Disease (Desnick_2010). These data do not allow any strong conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in <1% of the activity of the WT protein (Desnick_2010). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV000778333 SCV002092268 uncertain significance Niemann-Pick disease, type A 2021-03-03 no assertion criteria provided clinical testing

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