Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001378395 | SCV001575948 | likely pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2020-08-11 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMPD1-related conditions. 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.Leu304 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1391960, 26499107, 8401540, 10464620). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 sequence change replaces leucine with phenylalanine at codon 304 of the SMPD1 protein (p.Leu304Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. |