Submissions for variant NM_000543.5(SMPD1):c.788T>A (p.Leu263Ter)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248867	SCV001422542	pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Leu263Ter variant in SMPD1 (also known as p.Leu261Ter due to a difference in cDNA numbering) has been reported in 1 individual of Indian descent with Niemann-Pick disease (PMID: 1618760) and has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074120). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariaitonID: 2984) as Pathogenic by OMIM. In vitro functional studies provide some evidence that the p.Leu263Ter variant may impact protein activity (PMID: 1618760). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 263, 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 presence of this variant in an affected homozygote increases the likelihood that the p.Leu263Ter variant is pathogenic (PMID: 1618760). The phenotype of an individual homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal (PMID: 1618760). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction that it causes loss of function, in vitro functional studies, its presence in a homozygous individual, and the phenotype of a patient with the variant being highly specific for disease. ACMG/AMP Criteria applied: PVS1, PS3, PM2, PM3_supporting, PP4 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390954	SCV001592861	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-09-19	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs120074120, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 1618760, 27338287). This variant is also known as L261X. ClinVar contains an entry for this variant (Variation ID: 2984). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Leu263*) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801).
OMIM	RCV000003118	SCV000023276	pathogenic	Niemann-Pick disease, type A	1992-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000003118	SCV002091697	pathogenic	Niemann-Pick disease, type A	2017-03-17	no assertion criteria provided	clinical testing

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