ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.730G>T (p.Gly244Ter)

dbSNP: rs120074122
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409705 SCV000486207 likely pathogenic Niemann-Pick disease, type A 2016-04-14 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248873 SCV001422548 pathogenic Sphingomyelin/cholesterol lipidosis 2020-01-22 criteria provided, single submitter curation The p.Gly244Ter variant in SMPD1 (also known as p.Gly242Ter due to a difference in cDNA numbering) has been reported in 1 individual with Niemann-Pick disease (PMID: 29966168) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. This variant has been reported in ClinVar (VariationID: 370798) as likely pathogenic by Counsyl. This nonsense variant leads to a premature termination codon at position 244, which is predicted to lead to a truncated or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 29966168). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction it causes loss of function, its absence in the general population, and the phenotype of an individual with the variant being highly specific for the disease. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PP4 (Richards 2015).
Revvity Omics, Revvity RCV001782872 SCV002020765 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000409705 SCV005052848 pathogenic Niemann-Pick disease, type A 2024-02-13 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund RCV001782872 SCV005198300 pathogenic not provided 2023-08-22 criteria provided, single submitter clinical testing

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