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

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001976267	SCV002263185	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2025-01-27	criteria provided, single submitter	clinical testing	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). 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 missense change has been observed in individual(s) with acid sphingomyelinase deficiency (PMID: 23356216, 33675270). ClinVar contains an entry for this variant (Variation ID: 1475471). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
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.