Submissions for variant NM_000543.5(SMPD1):c.83C>T (p.Pro28Leu)

gnomAD frequency: 0.00001  dbSNP: rs556155962

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000728133	SCV000855667	likely benign	not specified	2017-07-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000915596	SCV001060811	benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001107111	SCV001264242	uncertain significance	Niemann-Pick disease, type A	2017-04-27	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV003165955	SCV003911737	likely benign	Inborn genetic diseases	2022-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357849	SCV001553438	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SMPD1 p.Pro28Leu variant was not identified in the literature but was identified in dbSNP (ID: rs556155962) and ClinVar (classified as likely benign by EGL Genetics). The variant was identified in control databases in 143 of 275324 chromosomes (2 homozygous) at a frequency of 0.0005194 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 140 of 30476 chromosomes (freq: 0.004594), Other in 1 of 7038 chromosomes (freq: 0.000142), African in 1 of 23448 chromosomes (freq: 0.000043) and Latino in 1 of 35150 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or European (non-Finnish) populations. The p.Pro28 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV001107111	SCV002091653	benign	Niemann-Pick disease, type A	2017-05-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003908018	SCV004719664	likely benign	SMPD1-related disorder	2022-03-28	no assertion criteria provided	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).