Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000169278 | SCV000220585 | likely pathogenic | Niemann-Pick disease, type A | 2014-08-10 | criteria provided, single submitter | literature only | |
Eurofins Ntd Llc |
RCV000594578 | SCV000700337 | pathogenic | not provided | 2017-03-06 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000689686 | SCV000817349 | pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2023-11-21 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 247 of the SMPD1 protein (p.Gly247Ser). This variant is present in population databases (rs587779408, gnomAD 0.007%). This missense change has been observed in individuals with Niemann-Pick disease (PMID: 12369017, 15221801, 15234149, 15241805, 23252888, 24767253). This variant is also known as p.Gly245Ser. ClinVar contains an entry for this variant (Variation ID: 100731). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 15241805). This variant disrupts the p.Gly247 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 23430884), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
Broad Center for Mendelian Genomics, |
RCV001248881 | SCV001422561 | pathogenic | Sphingomyelin/cholesterol lipidosis | 2020-01-22 | criteria provided, single submitter | curation | The p.Gly247Ser variant in SMPD1 (also known as p.Gly245Ser due to a difference in cDNA numbering) has been reported in at least 12 individuals with Niemann-Pick disease (PMID: 15234149, 12369017, 23252888, 24767253, 15221801, 19405096, 15241805) and has been identified in 0.004% (5/112836) of European (non-Finnish) chromosomes and 0.003% (1/34526) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587779408). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The presence of this variant in the homozygous state and in combination with reported pathogenic variants in individuals with Niemann-Pick disease increases the likelihood that the p.Arg247Ser variant is pathogenic (PMID: 15234149, 12369017, 23252888, 24767253, 15221801, 19405096, 15241805). The phenotype of individuals compound heterozygous for this variant is highly specific for Niemann-Pick based on acid sphingomyelinase activity in leukocytes or fibroblasts being <10%, consistent with disease (PMID: 23252888, 15241805). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on multiple occurrences in the homozygous state and with pathogenic SMPD1 variants in affected individuals and low frequency in the general population. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4 (Richards 2015). |
Baylor Genetics | RCV000169278 | SCV001527397 | pathogenic | Niemann-Pick disease, type A | 2024-03-26 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000594578 | SCV001794629 | pathogenic | not provided | 2019-09-10 | criteria provided, single submitter | clinical testing | Also known as G245S using alternate nomenclature; In one cohort of 15 patients with type A or B Niemann-Pick disease, G247S accounted for 12% of the pathogenic variants identified (Irun et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 31980526, 30223864, 23430884, 19405096, 23252888, 15241805, 24767253, 15221801, 15234149, 12369017, 30985853) |
Revvity Omics, |
RCV000594578 | SCV002020763 | pathogenic | not provided | 2019-05-24 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001248881 | SCV002103541 | pathogenic | Sphingomyelin/cholesterol lipidosis | 2022-02-16 | criteria provided, single submitter | clinical testing | Variant summary: SMPD1 c.739G>A (p.Gly247Ser) results in a non-conservative amino acid change located in the apaH type Calcineurin-like phosphoesterase domain (IPR004843) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248600 control chromosomes (gnomAD). The variant, c.739G>A (aka c.733G>A (p.G245S)) has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Niemann-Pick Disease (e.g. Simonaro_2002, Pittis_2004, Ricci_2004, Irun_2013). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, demonstrating a severely decreased residual enzyme activity (i.e. less than 10%) in patient derived fibroblasts and leukocytes (Pittis_2004, Irun_2013). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Unidad de Diagnostico y Tratamiento de Errores Congenitos del Metabolismo. |
RCV000087097 | SCV000119954 | pathogenic | Ceroid lipofuscinosis, neuronal, 6A | no assertion criteria provided | research | ||
Natera, |
RCV001248881 | SCV001455812 | likely pathogenic | Sphingomyelin/cholesterol lipidosis | 2020-09-16 | no assertion criteria provided | clinical testing |