Submissions for variant NM_000543.5(SMPD1):c.1550A>T (p.Glu517Val)

gnomAD frequency: 0.00284  dbSNP: rs142787001

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179328	SCV000231560	likely benign	not specified	2017-01-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000962425	SCV000605228	uncertain significance	not provided	2023-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179328	SCV000920238	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1550A>T (p.Glu517Val) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 251358 control chromosomes, predominantly at a frequency of 0.0037 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.65 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 a benign polymorphism found primarily in populations of Non-Finnish European originc.1550A>T has been reported in the literature in compound heterozygous individuals affected with Niemann-Pick Disease Type A (e.g. Wittmann_2012, Wasserstein_2015) and in several other patients without strong evidence for causality (e.g. Simonaro_2002, Zampieri_2015, Clark_2015). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type A and indicate that the variant may be associated with disease. 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: 12369017, 24767253, 23430949, 26499107, 26049896, 25933391).Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; eight submitters classified the variant as uncertain significance, while two classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae	RCV001081864	SCV001109504	likely benign	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000962425	SCV001148166	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing	SMPD1: PS4:Supporting
Illumina Laboratory Services, Illumina	RCV001107855	SCV001265042	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249037	SCV001422972	uncertain significance	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Glu517Val variant in SMPD1 (also known as p.Glu515Val due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 23430949, 26049896) and has been identified in 0.410% (529/129080) of European (non-Finnish) chromosomes, including 2 homozygotes, 0.192% (68/35430) of Latino chromosomes, and 0.108% (27/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142787001). This variant has also been reported in ClinVar (VariationID: 198094) as likely benign by EGL Genetic Diagnostics and as a VUS by ARUP Laboratories and Integrated Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported pathogenic variant and in an individual with Niemann-Pick disease increases the likelihood that the p.Glu517Val variant is pathogenic (VariationID: 2994; PMID: 23430949). In summary, the clinical significance of the p.Glu517Val variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3, PM3_Supporting (Richards 2015).
Centogene AG - the Rare Disease Company	RCV001786338	SCV002028334	uncertain significance	Niemann-Pick disease, type B	2018-06-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000962425	SCV002541123	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing	BS1, PP3
GeneDx	RCV000962425	SCV003194900	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing	Reported as E515V due to the use of alternative nomenclature in association with Niemann-Pick disease; however, additional information was not provided (Simonaro et al., 2002); Reported in association with Parkinson disease; however, additional information was not provided and the variant was observed in unaffected control individuals (Robak et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31122880, 23430949, 26049896, 34426522, 12369017, 29140481, 35747619, 30788890)
PreventionGenetics, part of Exact Sciences	RCV003967440	SCV004789061	likely benign	SMPD1-related condition	2022-02-03	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.	RCV001249037	SCV001452643	uncertain significance	Sphingomyelin/cholesterol lipidosis	2017-05-04	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000962425	SCV001806957	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000962425	SCV001928360	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000962425	SCV001974273	uncertain significance	not provided		no assertion criteria provided	clinical testing