Submissions for variant NM_000543.5(SMPD1):c.731G>C (p.Gly244Ala)

dbSNP: rs2134011288

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002049634	SCV002310173	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2021-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with alanine at codon 244 of the SMPD1 protein (p.Gly244Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of acid sphingomyelinase deficiency (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. 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.Gly244 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 1618760), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690233	SCV005185136	uncertain significance	not specified	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.731G>C (p.Gly244Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.731G>C in individuals affected with Niemann-Pick Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1524692). Based on the evidence outlined above, the variant was classified as uncertain significance.