ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1550A>T (p.Glu517Val) (rs142787001)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000179328 SCV000231560 likely benign not specified 2017-01-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283288 SCV000605228 uncertain significance none provided 2020-04-07 criteria provided, single submitter clinical testing The p.Glu517Val variant was reported in a patient with clinical diagnosis of Niemann-Pick type B (reported as E515V in Simonaro 2002). However, there was no clear information available in this publication if a second SMPD1 variant was identified in the particular patient. p.Glu517Val variant was also reported in a heterozygous form in an individual with low clinical suspicion for lysosomal storage disorder (Fernandez-Mamiesse 2014) and in a brain autopsy sample with confirmed Lewy body disease (Clark 2015). This variant (rs142787001) is listed in the Exome Aggregation Consortium Browser at an allele frequency of 0.3 percent (identified in 221 out of 66,726 chromosomes) in non-Finnish European populations. This variant was also identified by another laboratory with current classification of uncertain significance in ClinVar Database. Glutamic acid 517 is moderately conserved considering 12 species (Alamut software v.2.7.1) and computational prediction programs support the impact on the protein (SIFT: damaging, PolyPhen-2: probably damaging, and MutationTaster: disease causing). Based on the available information, there is not enough evidence to determine the clinical significance of the p.Glu517Val variant with certainty.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000179328 SCV000920238 uncertain significance not specified 2017-11-07 criteria provided, single submitter clinical testing Variant summary: The SMPD1 c.1550A>T (p.Glu517Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 682/277056 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.004085 (517/126550). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic SMPD1 variant (0.0022361), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. It has been reported in multiple affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this likely benign or variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV001081864 SCV001109504 likely benign Niemann-Pick disease, type B; Niemann-Pick disease, type A 2020-12-04 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000962425 SCV001148166 likely pathogenic not provided 2016-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Institute Rare Disease Group, Broad Institute RCV001249037 SCV001422972 uncertain significance Sphingomyelin/cholesterol lipidosis 2020-01-22 no assertion criteria provided 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).
Natera, Inc. RCV001249037 SCV001452643 uncertain significance Sphingomyelin/cholesterol lipidosis 2017-05-04 no assertion criteria provided clinical testing

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