ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.410G>A (p.Arg137Gln) (rs587778818)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000056176 SCV000800509 uncertain significance Cholestanol storage disease 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV000056176 SCV000960176 pathogenic Cholestanol storage disease 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 137 of the CYP27A1 protein (p.Arg137Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587778818, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from another pathogenic variant in a patient affected with cerebrotendinous xanthomatosis (PMID: 28623566). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been observed in several additional individuals affected with cerebrotendinous xanthomatosis (PMID: 20558929, 29269672, 28623566). This variant is known as p.Arg104Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 65929). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg137 amino acid residue in CYP27A1. Another variant that disrupts this residue has been observed in affected individuals (PMID: 8006521, 17697869), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001267947 SCV001446469 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056176 SCV001482211 pathogenic Cholestanol storage disease 2021-02-02 criteria provided, single submitter clinical testing Variant summary: CYP27A1 c.410G>A (p.Arg137Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251136 control chromosomes. c.410G>A has been reported in the literature in multiple individuals affected with Cerebrotendinous Xanthomatosis (e.g. Nozue_2010, Tada_2018, Tao_2019). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000056176 SCV000087264 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.

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