ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.667T>G (p.Cys223Gly)

dbSNP: rs1847923379
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital RCV001281403 SCV001468708 likely pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2020-12-30 criteria provided, single submitter clinical testing
Invitae RCV001281403 SCV004583729 likely pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2023-08-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 223 of the SMPD1 protein (p.Cys223Gly). 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: 33675270). ClinVar contains an entry for this variant (Variation ID: 992687). 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.Cys223 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27338287, 34273913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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