Submissions for variant NM_000543.5(SMPD1):c.1673T>C (p.Leu558Pro)

dbSNP: rs875989836

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765358	SCV004570149	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 558 of the SMPD1 protein (p.Leu558Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick disease type A (PMID: 26851525). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1670T>C (p.L557P). ClinVar contains an entry for this variant (Variation ID: 225624). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701278	SCV005204354	uncertain significance	not specified	2024-06-12	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1673T>C (p.Leu558Pro) 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 251484 control chromosomes. c.1673T>C has been reported in the literature in individuals affected with Niemann-Pick Disease (e.g. Ding_2016, Hu_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is also kown as c.1670T>C(p.L557P). The following publications have been ascertained in the context of this evaluation (PMID: 26377108, 26851525, 33675270). ClinVar contains an entry for this variant (Variation ID: 225624). Based on the evidence outlined above, the variant was classified as uncertain significance.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV003765358	SCV005417200	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PM3_Supporting
Laboratory of Metabolic Disorders, Peking University First Hospital	RCV000211547	SCV000267613	pathogenic	Niemann-Pick disease, type A	2015-05-20	no assertion criteria provided	research