ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.901G>A (p.Val301Ile) (rs2723669)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000293370 SCV000372935 likely benign 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000592219 SCV000704670 benign not specified 2016-12-16 criteria provided, single submitter clinical testing
Invitae RCV001081788 SCV001049192 benign Niemann-Pick disease, type B; Niemann-Pick disease, type A 2020-12-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000675395 SCV000801065 likely benign not provided 2018-02-08 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001249056 SCV001423003 likely benign Sphingomyelin/cholesterol lipidosis 2020-01-22 no assertion criteria provided curation The p.Val301Ile variant in SMPD1 (also known as p.Val299Ile due to a difference in cDNA numbering) has not been previously reported in individuals with Niemann-Pick disease, but has been identified in 1.166% (291/24858) of African chromosomes, including 1 homozygote, 0.116% (41/35436) of Latino chromosomes, and 0.0196% (6/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs2723669. This variant has also been reported in ClinVar (VariationID: 305201) as a VUS by Illumina Clinical Services Laboratory, as likely benign by Mayo Clinic Genetic Testing Laboratories, and as Benign by EGL Genetic 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, BP4 (Richards 2015).

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