Submissions for variant NM_000543.5(SMPD1):c.973C>T (p.Pro325Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002857215	SCV003224925	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2022-09-22	criteria provided, single submitter	clinical testing	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. 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. This variant disrupts the p.Pro325 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15545621, 23430512, 26084044). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 325 of the SMPD1 protein (p.Pro325Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004765577	SCV005380753	uncertain significance	not specified	2024-08-09	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.973C>T (p.Pro325Ser) results in a non-conservative amino acid change in 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 251464 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.973C>T 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: 2020354). Based on the evidence outlined above, the variant was classified as uncertain significance.