Submissions for variant NM_000543.5(SMPD1):c.1599G>A (p.Pro533=)

gnomAD frequency: 0.00004  dbSNP: rs552841217

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000261207	SCV000340485	likely benign	not specified	2016-03-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000305957	SCV000372944	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000970644	SCV001118234	benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249035	SCV001422970	likely benign	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The c.1599G>A (p.Pro533=) variant in SMPD1 (also known as p.Pro531= due to a difference in cDNA numbering) has not been previously reported in individuals with Niemann-Pick disease, but has been identified in 0.477% (146/30616) of South Asian chromosomes, including 1 homozygote, 0.012% (3/24968) of African chromosomes, and 0.005% (1/19954) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs552841217). This variant has also been reported in ClinVar (VariationID: 286896) as a VUS by Illumina Clinical Services Laboratory and as likely benign by EGL Genetics Diagnostics. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP7, BP4 (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV003401256	SCV004135843	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	SMPD1: BP4, BP7
Natera, Inc.	RCV000305957	SCV002092286	likely benign	Niemann-Pick disease, type A	2018-04-12	no assertion criteria provided	clinical testing