ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.1016C>T (p.Thr339Met) (rs121908102)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000004487 SCV000427475 pathogenic Cholestanol storage disease 2017-04-27 criteria provided, single submitter clinical testing The CYP27A1 c.1016C>T (p.Thr339Met) variant has been reported in six studies in which it was found in a homozygous state in five individuals and in a compound heterozygous state in four individuals, all with cerebrotendinous xanthomatosis, and in a heterozygous state in four unaffected family members (Reshef et al. 1994; Guyant-Marechal et al. 2005; Pilo-de-la-Fuente et al. 2011; Caroppo et al. 2013; Schabhuttl et al. 2014; Huidekoper et al. 2016). The p.Thr339Met variant was absent from 100 controls and is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. The Thr306 residue is conserved and located in the heme-binding site of the protein. Based on the evidence, the p.Thr339Met variant is classified as pathogenic for cerebrotendinous xanthomatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genetic Services Laboratory, University of Chicago RCV000004487 SCV000594288 likely pathogenic Cholestanol storage disease 2016-05-19 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000518366 SCV000613048 likely pathogenic not provided 2017-05-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000004487 SCV000893577 pathogenic Cholestanol storage disease 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000004487 SCV001136215 pathogenic Cholestanol storage disease 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000004487 SCV001205735 pathogenic Cholestanol storage disease 2019-08-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 339 of the CYP27A1 protein (p.Thr339Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs121908102, ExAC 0.01%). This variant has been observed to segregate with cerebrotendinous xanthomatosis in a family (PMID: 8014582) and has also been observed in several individuals affected with cerebrotendinous xanthomatosis (PMID: 8014582, 27858369, 26156051, 24627108). This variant is also known as p.Thr306Met in the literature. ClinVar contains an entry for this variant (Variation ID: 4266). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004487 SCV000024661 pathogenic Cholestanol storage disease 2005-12-01 no assertion criteria provided literature only
GeneReviews RCV000004487 SCV000087126 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000004487 SCV001132160 pathogenic Cholestanol storage disease 2016-12-01 no assertion criteria provided clinical testing

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