Submissions for variant NM_000543.5(SMPD1):c.1625G>A (p.Arg542Gln)

gnomAD frequency: 0.00629  dbSNP: rs113467489

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000270672	SCV000372946	likely 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 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	RCV000967675	SCV001115077	benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001718618	SCV001947279	benign	not provided	2021-06-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29029963)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222483	SCV002500209	likely benign	not specified	2022-03-08	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1625G>A (p.Arg542Gln) results in a conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 251356 control chromosomes, predominantly at a frequency of 0.023 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV000270672	SCV002092289	benign	Niemann-Pick disease, type A	2017-05-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003930292	SCV004739824	benign	SMPD1-related disorder	2019-08-29	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).