Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001984353 | SCV002281377 | likely pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2021-03-25 | criteria provided, single submitter | clinical testing | 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.Phe465 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12556236, 22818240, 27338287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 has not been reported in the literature in individuals with SMPD1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 465 of the SMPD1 protein (p.Phe465Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003402025 | SCV004122795 | uncertain significance | not specified | 2023-10-12 | criteria provided, single submitter | clinical testing | Variant summary: SMPD1 c.1395T>G (p.Phe465Leu) results in a non-conservative amino acid change located in the Acid sphingomyelinase/endopolyphosphatase, metallophosphatase domain (IPR041805) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251494 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.1395T>G in individuals affected with Niemann-Pick Disease and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. |