Submissions for variant NM_000543.5(SMPD1):c.1071C>T (p.Ala357=)

gnomAD frequency: 0.00571  dbSNP: rs72896268

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079188	SCV000111057	benign	not specified	2013-08-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079188	SCV000305088	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000394529	SCV000372937	likely benign	Niemann-Pick disease, type A	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082924	SCV000755907	benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-02-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249054	SCV001423000	likely benign	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The c.1071C>T (p.Ala357=) variant in SMPD1 (also known as p.Ala355= due to a difference in cDNA numbering) has not been previously reported in individuals with Niemann-Pick disease, but has been identified in 1.062% (110/10360) of Ashkenazi Jewish chromosomes, 0.807% (1037/128468) of European (non-Finnish) chromosomes, including 9 homozygotes, and 0.378% (134/35428) of Latino chromosomes. This variant has also been reported in ClinVar (VariationID: 93310) as a VUS by Illumina Clinical Services Laboratory, as likely benign by PreventionGenetics, and as benign by Invitae, EGL Genetic Diagnostics, and Mayo Clinic Genetic Testing Laboratories. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BP7 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000079188	SCV001442606	benign	not specified	2020-10-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000675396	SCV001502022	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	SMPD1: BS2
Genome-Nilou Lab	RCV000394529	SCV001716378	benign	Niemann-Pick disease, type A	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000675396	SCV001859889	benign	not provided	2021-01-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415576	SCV002718915	likely benign	Inborn genetic diseases	2022-02-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Breakthrough Genomics, Breakthrough Genomics	RCV000675396	SCV005223222	likely benign	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000675396	SCV000801066	benign	not provided	2015-10-22	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000394529	SCV002092260	benign	Niemann-Pick disease, type A	2017-03-29	no assertion criteria provided	clinical testing