ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1497_1498inv (p.Tyr500His)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001976267 SCV002263185 pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2023-04-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1475471). This missense change has been observed in individual(s) with acid sphingomyelinase deficiency (PMID: 23356216, 33675270). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 500 of the SMPD1 protein (p.Tyr500His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226517 SCV003922727 pathogenic Sphingomyelin/cholesterol lipidosis 2023-03-18 criteria provided, single submitter clinical testing Variant summary: SMPD1 c.1497_1498delinsAC (p.Tyr500His) results in a conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251212 control chromosomes (gnomAD). c.1497_1498delinsAC has been reported in the literature as a biallelic genotype in multiple individuals affected with Niemann-Pick Disease (e.g. Zhang_2013, Hu_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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