ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.739G>A (p.Gly247Ser)

gnomAD frequency: 0.00003  dbSNP: rs587779408
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Total submissions: 10
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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 (ga) RCV000594578 SCV000700337 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing
Invitae 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 Institute Rare Disease Group, Broad Institute 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 2018-09-27 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx 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, 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, LabCorp 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. Hospital Clínico Universitário de Santiago de Compostela RCV000087097 SCV000119954 pathogenic Ceroid lipofuscinosis, neuronal, 6A no assertion criteria provided research
Natera, Inc. RCV001248881 SCV001455812 likely pathogenic Sphingomyelin/cholesterol lipidosis 2020-09-16 no assertion criteria provided clinical testing

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