ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1589G>C (p.Gly530Ala) (rs35122256)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000370628 SCV000344411 likely benign not specified 2016-08-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000399404 SCV000372943 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 RCV001084821 SCV000755904 likely benign Niemann-Pick disease, type B; Niemann-Pick disease, type A 2020-12-04 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000675398 SCV000801071 uncertain significance not provided 2017-08-31 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001249036 SCV001422971 uncertain significance Sphingomyelin/cholesterol lipidosis 2020-01-22 no assertion criteria provided curation The p.Gly530Ala variant in SMPD1 (also known as p.Gly528Ala 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% (119/24970) of African chromosomes, 0.023% (8/35428) of African chromosomes, and 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs35122256). This variant has also been reported in ClinVar (VariationID: 289948) as likely benign by Invitae and EGL Genetic Diagnostics and as a VUS by Illumina Clinical Services Laboratory and Mayo Clinic Genetic Testing Laboratories. The Gly at position 530 is not highly conserved in mammals and evolutionary distant species, and 1 mammal (Prairie Vole) carries an Ala, raising the supporting that this change at this position may be tolerated. Additional computational prediction tools suggest that the variant is less likely to impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Gly530Ala variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015).

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