ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.409C>T (p.Arg137Trp) (rs72551312)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000056112 SCV000800561 uncertain significance Cholestanol storage disease 2017-07-12 criteria provided, single submitter clinical testing
Invitae RCV000056112 SCV000956867 pathogenic Cholestanol storage disease 2020-08-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 137 of the CYP27A1 protein (p.Arg137Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs72551312, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with cerebrotendinous xanthomatosis (PMID: 21553098). This variant has been observed to segregate with cerebrotendinous xanthomatosis in a family (PMID: 8006521). This variant has also been reported to ClinVar contains an entry for this variant (Variation ID: 65867). This variant is also known as p.Arg104Trp in the literature. These findings are consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. 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: 20558929, 29269672, 28623566), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268892 SCV001448132 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
GeneReviews RCV000056112 SCV000087189 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.

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