Submissions for variant NM_000543.5(SMPD1):c.1735G>A (p.Gly579Ser)

gnomAD frequency: 0.00001  dbSNP: rs120074119

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000003116	SCV001163317	likely pathogenic	Niemann-Pick disease, type A	2024-01-27	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248875	SCV001422550	pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Gly579Ser variant in SMPD1 (also known as p.Gly577Ser due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 1718266, 15877209, 16151905) and has been identified in 0.002% (2/113736) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074119). 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 (VariationID: 2982) as pathogenic by OMIM. In vitro functional studies provide some evidence that the p.Gly579Ser variant may impact protein function (PMID: 1718266). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in 1 affected homozygote and in combination with a reported pathogenic variant in an individual with Niemann-Pick disease increases the likelihood that the p.Gly579Ser variant is pathogenic (VariationID: 2994; PMID: 1718266, 15877209, 16151905). The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyselinase activity being <10% of normal, consistent with disease (PMID: 15877209). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on in vitro functional studies and its presence in individuals with phenotypes specific for disease. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851600	SCV002232702	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-06-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 2982). This variant is also known as G577S. This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 1718266, 15877209). This variant is present in population databases (rs120074119, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 579 of the SMPD1 protein (p.Gly579Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001248875	SCV002555608	pathogenic	Sphingomyelin/cholesterol lipidosis	2022-06-03	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1735G>A (p.Gly579Ser) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251448 control chromosomes. c.1735G>A has been reported in the literature in individuals affected with Niemann-Pick Disease (example, Ferlinz_1991, Pavlu-Pereira_2005, Hu_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Ferlinz_1991). The most pronounced variant effect results in complete loss of enzymatic activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000003116	SCV000023274	pathogenic	Niemann-Pick disease, type A	1991-09-30	no assertion criteria provided	literature only