Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000664755 | SCV000788764 | uncertain significance | Niemann-Pick disease, type A | 2016-12-29 | criteria provided, single submitter | clinical testing | |
| Diagnostics Division, |
RCV001527434 | SCV001738439 | likely pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2021-04-25 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV001527434 | SCV002292017 | pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2022-08-16 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 20386867, 34273913). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 577 of the SMPD1 protein (p.His577Arg). ClinVar contains an entry for this variant (Variation ID: 550112). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His577 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 12712061, 20386867, 26499107), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 20386867). 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. |
| Mendelics | RCV000664755 | SCV002517423 | likely pathogenic | Niemann-Pick disease, type A | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV003133487 | SCV003808270 | likely pathogenic | not provided | 2022-11-03 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330876 | SCV004037623 | likely pathogenic | Sphingomyelin/cholesterol lipidosis | 2023-08-28 | criteria provided, single submitter | clinical testing | Variant summary: SMPD1 c.1730A>G (p.His577Arg) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes (gnomAD). c.1730A>G has been reported in the literature in compound heterozygous and homozygous individuals affected with Niemann-Pick Disease (Desnick_2010, Deshpande_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and p.H577R had less than 1% of expressed wild-type activity (Desnick_2010). The following publications have been ascertained in the context of this evaluation (PMID: 34273913, 20386867, 27435900). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1, likely pathogenic (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV000664755 | SCV005052836 | likely pathogenic | Niemann-Pick disease, type A | 2024-03-29 | criteria provided, single submitter | clinical testing |