Submissions for variant NM_000543.5(SMPD1):c.714A>G (p.Ala238=)

gnomAD frequency: 0.03664  dbSNP: rs2682091

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000334737	SCV000331130	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000357990	SCV000372928	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556311	SCV000631414	benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000334737	SCV000918246	benign	not specified	2018-06-04	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.714A>G alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.011 in 273774 control chromosomes in the gnomAD database, including 170 homozygotes. The observed variant frequency is approximately 4.96 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A phenotype (0.0022), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.714A>G in individuals affected with Niemann-Pick Disease Type A and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000675392	SCV000971109	benign	not provided	2018-06-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV002365293	SCV002662320	likely benign	Inborn genetic diseases	2022-06-02	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	RCV000675392	SCV005323427	benign	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000675392	SCV000801062	benign	not provided	2017-08-30	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000357990	SCV002091692	benign	Niemann-Pick disease, type A	2017-05-06	no assertion criteria provided	clinical testing