ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.586_587del (p.Ser196fs)

dbSNP: rs758739930
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000779307 SCV000915889 uncertain significance Cholestanol storage disease 2018-04-23 criteria provided, single submitter clinical testing The CYP27A1 c.586_587delAG (p.Ser196CysfsTer91) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for cerebrotendinous xanthomatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000779307 SCV001375858 pathogenic Cholestanol storage disease 2023-06-15 criteria provided, single submitter clinical testing This variant is present in population databases (rs758739930, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 632347). This variant has not been reported in the literature in individuals affected with CYP27A1-related conditions. This sequence change creates a premature translational stop signal (p.Ser196Cysfs*91) in the CYP27A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779307 SCV002570660 likely pathogenic Cholestanol storage disease 2022-07-15 criteria provided, single submitter clinical testing Variant summary: CYP27A1 c.586_587delAG (p.Ser196CysfsX91) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in Cerebrotendinous xanthomatosis in HGMD. The variant allele was found at a frequency of 8e-06 in 251476 control chromosomes. To our knowledge, no occurrence of c.586_587delAG in individuals affected with Cerebrotendinous Xanthomatosis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000779307 SCV004192657 likely pathogenic Cholestanol storage disease 2023-10-09 criteria provided, single submitter clinical testing

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