ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.380G>A (p.Arg127Gln) (rs376230356)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000056111 SCV000754986 pathogenic Cholestanol storage disease 2018-03-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 127 of the CYP27A1 protein (p.Arg127Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs376230356, ExAC 0.003%). This variant has been reported as homozygous or in combination with another CYP27A1 variant in several individuals and in a single family affected with cerebrotendinous xanthomatosis (CTX) (PMID: 8730343, 10775536, Invitae). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in two siblings affected with CTX (PMID: 8730343). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as p.Arg94Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 65866). 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. A different missense substitution at this codon (p.Arg127Trp) has been determined to be pathogenic (PMID: 28623566, 23659550, 27455001, 10430841, 10775536). This suggests that the arginine residue is critical for CYP27A1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000056111 SCV000790215 likely pathogenic Cholestanol storage disease 2017-03-08 criteria provided, single submitter clinical testing
GeneReviews RCV000056111 SCV000087188 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.

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