Submissions for variant NM_000543.5(SMPD1):c.1529C>T (p.Ser510Phe)

gnomAD frequency: 0.00001  dbSNP: rs200652683

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664533	SCV000788511	uncertain significance	Niemann-Pick disease, type A	2017-01-06	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000731478	SCV000859302	uncertain significance	not provided	2018-01-31	criteria provided, single submitter	clinical testing
Invitae	RCV001085567	SCV001118349	benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000664533	SCV001265041	likely benign	Niemann-Pick disease, type A	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Revvity Omics, Revvity	RCV000731478	SCV003822013	uncertain significance	not provided	2021-03-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488785	SCV004242005	likely benign	not specified	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1529C>T (p.Ser510Phe) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 251428 control chromosomes, predominantly at a frequency of 0.0064 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 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 South Asian origin. c.1529C>T has been reported in the literature in individuals affected with Niemann-Pick Disease (Ranganath_2016, Deshpande_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34273913, 27338287). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as pathogenic (n=1), uncertain significance (n=3), likely benign (n=2) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003945695	SCV004761962	likely benign	SMPD1-related condition	2023-12-08	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001271474	SCV001452642	likely benign	Sphingomyelin/cholesterol lipidosis	2020-04-14	no assertion criteria provided	clinical testing
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV000664533	SCV001738435	pathogenic	Niemann-Pick disease, type A	2021-04-25	flagged submission	research