ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1556A>G (p.Tyr519Cys)

dbSNP: rs371837210
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000504182 SCV000588361 uncertain significance Niemann-Pick disease, type A 2020-05-03 criteria provided, single submitter clinical testing
Counsyl RCV000504182 SCV000794352 uncertain significance Niemann-Pick disease, type A 2017-10-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002524354 SCV003439609 likely pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2022-03-03 criteria provided, single submitter clinical testing 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. 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: 437453). This variant is also known as p.Y517C. This missense change has been observed in individuals with Niemann-Pick disease type A (PMID: 15221801, 27338287). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 519 of the SMPD1 protein (p.Tyr519Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689767 SCV005185752 uncertain significance not specified 2024-05-15 criteria provided, single submitter clinical testing Variant summary: SMPD1 c.1556A>G (p.Tyr519Cys; also described as c.1550A>G; p.Y517C in the literature) results in a non-conservative amino acid change located in the sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251342 control chromosomes (gnomAD). c.1556A>G has been reported in the literature in individuals affected with Niemann-Pick Disease (Ricci_2004, Ranganath_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27338287, 15221801). ClinVar contains an entry for this variant (Variation ID: 437453). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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