Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001071343 | SCV001236640 | pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2022-08-09 | criteria provided, single submitter | clinical testing | This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 465 of the SMPD1 protein (p.Phe465Ser). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12556236, 22818240, 27338287, 33675270). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 864212). This variant is also known as g.3337T > C (F463S). |
| Diagnostics Division, |
RCV001527428 | SCV001738431 | likely pathogenic | Niemann-Pick disease, type A | 2021-04-25 | criteria provided, single submitter | research | |
| Baylor Genetics | RCV001527428 | SCV005052835 | pathogenic | Niemann-Pick disease, type A | 2024-03-30 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005236584 | SCV005883188 | pathogenic | Sphingomyelin/cholesterol lipidosis | 2024-12-05 | criteria provided, single submitter | clinical testing | Variant summary: SMPD1 c.1394T>C (p.Phe465Ser) results in a non-conservative amino acid change located in the acid sphingomyelinase and related proteins, metallophosphatase domain (IPR041805) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251494 control chromosomes. c.1394T>C has been reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Niemann-Pick Disease (Hu_2021, Deshpande_2021, Sikora_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34273913, 33675270, 12556236). ClinVar contains an entry for this variant (Variation ID: 864212). Based on the evidence outlined above, the variant was classified as pathogenic. |