Submissions for variant NM_000543.5(SMPD1):c.887G>A (p.Arg296Gln)

gnomAD frequency: 0.01388  dbSNP: rs35824453

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175631	SCV000227155	benign	not specified	2015-05-20	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224205	SCV000280601	benign	not provided	2015-08-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000383492	SCV000372934	benign	Niemann-Pick disease, type A	2018-03-06	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	RCV000175631	SCV000920242	likely benign	not specified	2018-06-04	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.887G>A (p.Arg296Gln) results in a conservative amino acid change located in the Calcineurin-like ApaH type phosphoesterase domain of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0044 in 277234 control chromosomes in the gnomAD database, including 27 homozygotes. The observed variant frequency is approximately 1.96 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. c.887G>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type A. These report(s) do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type A. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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 likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081402	SCV001116891	benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000224205	SCV001888861	benign	not provided	2020-05-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15221801, 21228398, 20981092)
Mayo Clinic Laboratories, Mayo Clinic	RCV000224205	SCV002541122	uncertain significance	not provided	2022-01-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224205	SCV004135841	benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	SMPD1: BP4, BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000224205	SCV005223219	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000383492	SCV002092252	benign	Niemann-Pick disease, type A	2017-05-08	no assertion criteria provided	clinical testing