Submissions for variant NM_000543.5(SMPD1):c.1451C>A (p.Ala484Glu)

dbSNP: rs267607075

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780737	SCV000918249	pathogenic	not specified	2018-12-24	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1451C>A (p.Ala484Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246364 control chromosomes (gnomAD). c.1451C>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type A (Rodriguez-Pascau_2009). 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. The most pronounced variant effect results in <10% of normal activity (Rodriguez-Pascau_2009). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249038	SCV001422973	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-29	criteria provided, single submitter	curation	The p.Ala484Glu variant in SMPD1 (also known as p.Ala482Glu due to a difference in cDNA numbering) has been reported in 3 individuals with Niemann-Pick disease (PMID: 19405096) and has been identified in 0.001% (1/113758) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs267607075). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Ala484Glu variant may impact protein function (PMID: 19405096, 26499107). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 1 homozygote and in combination with a reported pathogenic variant in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Ala484Glu variant is pathogenic (VariationID: 198093; PMID: 19405096). One additional variant, resulting in a different amino acid change at the same position, p.Ala484Val, has been reported in association with disease in the literature (PMID: 23356216, 30912297). The phenotype of individuals homozygous and 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: 19405096). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP4 (Richards 2015).
DASA	RCV001824114	SCV002073744	likely pathogenic	Niemann-Pick disease, type B	2022-02-05	criteria provided, single submitter	clinical testing	The c.1451C>A;p.(Ala484Glu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 2995; OMIM: 607608.0016; PMID: 19405096) - PS4_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 19405096) - PS3_moderate. This variant is not present in population databases (rs267607075; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851602	SCV002179676	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-03-07	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: 2995). This variant is also known as c.1445C>A (p.A482E). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 19405096). This variant is present in population databases (rs267607075, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 484 of the SMPD1 protein (p.Ala484Glu).
Baylor Genetics	RCV000003130	SCV004205530	pathogenic	Niemann-Pick disease, type A	2022-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000003130	SCV000023288	pathogenic	Niemann-Pick disease, type A	2009-07-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000003130	SCV002092279	pathogenic	Niemann-Pick disease, type A	2017-03-17	no assertion criteria provided	clinical testing