Submissions for variant NM_000543.5(SMPD1):c.807C>T (p.Ala269=)

gnomAD frequency: 0.01598  dbSNP: rs35933246

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000295349	SCV000339598	benign	not specified	2016-02-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000322873	SCV000372930	benign	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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000295349	SCV000920244	benign	not specified	2018-06-04	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.807C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 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 0.0049 in 120406 control chromosomes, predominantly at a frequency of 0.056 within the African or African-American subpopulation in the ExAC database, including 19 homozygotes. The observed variant frequency within African or African-American control individuals in the ExAC database is approximately 25.14 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 a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.807C>T in individuals affected with Niemann-Pick Disease Type A and no experimental evidence demonstrating its impact on protein function have been reported. Two 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	RCV000844259	SCV000986307	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081401	SCV001116493	benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-31	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000844259	SCV005323428	benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000322873	SCV002091698	benign	Niemann-Pick disease, type A	2017-06-14	no assertion criteria provided	clinical testing