Submissions for variant NM_000543.5(SMPD1):c.441G>A (p.Val147=)

gnomAD frequency: 0.00241  dbSNP: rs148944108

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000325277	SCV000340675	benign	not specified	2016-03-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000357086	SCV000372925	uncertain significance	Niemann-Pick disease, type A	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081186	SCV001118310	benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000970717	SCV001148165	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248936	SCV001422714	uncertain significance	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The c.441G>A (p.Val147=) variant in SMPD1 (also known as p.Val145= due to a difference in cDNA numbering) has not been previously reported in individuals with Niemann-Pick disease but has been identified in 0.585% (146/24956) of African chromosomes, 0.133% (47/35414) of Latino chromosomes, and 0.0147% (19/129008) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148944108). This variant has been reported in ClinVar as a VUS by Illumina and Benign by EGL Genetic Diagnostics (Variation ID: 287033). Computational tools do suggest an impact to splicing with the strong activation of a cryptic donor site. However, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the c.441G>A variant is uncertain. ACMG/AMP Criteria applied: BS1 (Richards 2015).
Natera, Inc.	RCV000357086	SCV002091677	likely benign	Niemann-Pick disease, type A	2017-05-05	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003957470	SCV004771488	likely benign	SMPD1-related disorder	2019-08-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).