Submissions for variant NM_000543.5(SMPD1):c.1106A>G (p.Tyr369Cys)

gnomAD frequency: 0.00002  dbSNP: rs372287825

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000292122	SCV000342071	uncertain significance	not provided	2016-05-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004584	SCV001163675	likely pathogenic	Niemann-Pick disease, type A		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001218398	SCV001390279	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-04-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 19405096). 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: 288073). This variant is also known as c.1100A>G, p.Y367C. This missense change has been observed in individual(s) with intermediate type Niemann-Pick disease (PMID: 19405096, 27338287, 28801223). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 369 of the SMPD1 protein (p.Tyr369Cys).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249051	SCV001422997	pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Tyr369Cys variant in SMPD1 (also known as p.Tyr367Cys due to a difference in cDNA numbering) has been reported in 3 individuals with Niemann-Pick disease, segregated with disease in 2 affected relatives from 1 family (PMID: 19405096, 28801223), and was absent from large population studies. This variant has also been reported in ClinVar (VariationID: 288073) as a VUS by EGL Genetic Diagnostics. In vitro functional studies provide some evidence that the p.Tyr369Cys variant may impact protein function (PMID: 19405096). 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 2 affected homozygotes and in combination with a reported pathogenic variant in an individual with Niemann-Pick disease increases the likelihood that the p.Tyr369Cys variant is pathogenic (VariationID: 100731; PMID: 19405096, 28801223). 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, consistent with disease (PMID: 28801223). 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, the presence of the variant in homozygotes and in combination with other pathogenic variants, and the phenotype of an individual with the variant being highly specific for disease. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV001004584	SCV001738423	likely pathogenic	Niemann-Pick disease, type A	2021-04-25	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249051	SCV004038906	pathogenic	Sphingomyelin/cholesterol lipidosis	2023-08-10	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1106A>G (p.Tyr369Cys) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249020 control chromosomes. c.1106A>G has been reported in the literature in multiple individuals affected with Niemann-Pick Disease, including being at a homozygous state or being seen with a second pathogenic variant (example: Rodriguez-Pascau_2009, Mercati_2017, Ranganath_2016, Hu_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <5% of normal activity (Rodriguez-Pascau_2009). The following publications have been ascertained in the context of this evaluation (PMID: 33675270, 28801223, 27338287, 19405096). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic n=2, Likely pathogenic n=1, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000292122	SCV005390348	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	Published functional studies in COS-7 cells show severely reduced enzyme activity (PMID: 19405096); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33675270, 28801223, 31576605, 19405096, 34273913, 26499107, 27338287)