ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.1214G>A (p.Arg405Gln) (rs121908099)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000004482 SCV000267284 likely pathogenic Cholestanol storage disease 2016-03-18 criteria provided, single submitter reference population
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726759 SCV000702839 pathogenic not provided 2017-12-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000004482 SCV000712211 pathogenic Cholestanol storage disease 2016-06-15 criteria provided, single submitter clinical testing The p.Arg405Gln variant in CYP27A1 has been reported in at least 3 families (1 h omozygous and 2 compound heterozygous) with cerebrotendinous xanthomatosis and s egregated with disease in 3 affected relatives from 2 families (Chen 1997, Suh 2 011). It has also been reported, in the compound heterozygous state, in 2 patie nts with the spinal form of the disease (Abe 2015, Yanagihashi 2016). . In vitr o functional studies provide some evidence that the p.Arg405Gln variant may impa ct protein function (Chen 1997). This variant has been identified in 8/121,382 o f chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs121908099). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrie r frequency. In summary, this variant meets our criteria to be classified as pat hogenic for cerebrotendinous xanthomatosis in an autosomal recessive manner, bas ed upon case observations, segregation studies, low frequency in controls and fu nctional evidence.
Invitae RCV000004482 SCV000954777 pathogenic Cholestanol storage disease 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 405 of the CYP27A1 protein (p.Arg405Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs121908099, ExAC 0.05%). This variant has been observed to be homozygous or in combination with another CYP27A1 variant in individuals affected with cerebrotendinous xanthomatosis (PMID: 28623566, 25941960, 26861945, 25447658, 29321515), and has been shown to segregate with disease in several families (PMID: 9186905, 14741198, 21958693). ClinVar contains an entry for this variant (Variation ID: 4260). Experimental studies have shown that this missense change disrupts CYP27A1 protein function (PMID: 9186905). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000004482 SCV001162938 pathogenic Cholestanol storage disease criteria provided, single submitter clinical testing
OMIM RCV000004482 SCV000024655 pathogenic Cholestanol storage disease 1997-05-01 no assertion criteria provided literature only
GeneReviews RCV000004482 SCV000087144 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000004482 SCV000789751 likely pathogenic Cholestanol storage disease 2017-02-16 no assertion criteria provided clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252459 SCV001428215 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing
Natera, Inc. RCV000004482 SCV001459898 pathogenic Cholestanol storage disease 2020-09-16 no assertion criteria provided clinical testing

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