ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.1183C>T (p.Arg395Cys) (rs121908096)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000275162 SCV000329815 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing The R395C pathogenic variant in the CYP27A1 gene has been reported previously, also in alternate nomenclature as R362C, in both the homozygous and compound heterozygous states in individuals with cerebrotendinous xanthomatosis (Cali et al., 1991; Pilo-de-la-Fuente et al, 2011; Smalley et al., 2015). Additionally, two other amino acid substitutions at the same position (R395S, R395H) have been reported in the Human Gene Mutation Database in association with cerebrotendinous xanthomatosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R395C variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R395C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico splice prediction programs predict this variant may damage or destroy the natural splice donor site in intron 6, possibly leading to abnormal gene splicing. In vitro functional studies showed no detectable enzyme activity in cells transfected with R362C cDNA (Cali et al., 1991). We interpret R395C as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000004477 SCV000427476 pathogenic Cholestanol storage disease 2017-04-28 criteria provided, single submitter clinical testing Across a selection of the available literature, the CYP27A1 c.1183C>T (p.Arg395Cys) variant has been reported in nine studies in which is found in a total of 20 individuals with cerebrotendinous xanthomatosis, including four in a homozygous state and 16 in a compound heterozygous state, and in at least 18 additional disease alleles of unknown zygosity (Cali et al. 1991; Verrips et al. 2000; Szlago et al. 2008; Pilo-de-la-Fuente et al. 2011; Lionnet et al. 2014; Smally et al. 2015; Varman et al. 2016; Huidekoper et al. 2016; Koopal et al. 2016). The p.Arg395Cys variant was absent from 310 control alleles but is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies by Cali et al. (1991) showed the p.Arg395Cys variant had no detectable sterol 27-hydroxylase enzyme activity when expressed in COS-M6 cells. Gupta et al. (2007) demonstrated in COS-1 cells that the variant resulted in lower levels of protein expression and disrupted the heme-binding domain, resulting in an inactive protein. Based on the collective evidence, the p.Arg395Cys variant is classified pathogenic for cerebrotendinous xanthomatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000275162 SCV000700806 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000004477 SCV000744173 likely pathogenic Cholestanol storage disease 2017-12-08 criteria provided, single submitter clinical testing
Invitae RCV000004477 SCV000754983 pathogenic Cholestanol storage disease 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 395 of the CYP27A1 protein (p.Arg395Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121908096, ExAC 0.03%). This variant has been reported as homozygous or in combination with another CYP27A1 variant in many individuals affected with cerebrotendinous xanthomatosis (PMID: 26156051, 2019602, 20402754, 21955034, 21645175, 10775536, 24746394, 26906304, 18227423). This variant is also known as p.Arg362Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 4255). Experimental studies have shown that this missense change abrogates CYP27A1 enzyme activity (PMID: 2019602). 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. Two different missense substitutions at this codon (p.Arg395Ser and p.Arg395His) have been reported in individuals affected with cerebrotendinous xanthomatosis (PMID: 9790667, 8950197). For these reasons, this variant has been classified as Pathogenic.
Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile RCV000004477 SCV000897998 pathogenic Cholestanol storage disease 2014-04-07 criteria provided, single submitter research This patient is a compound heterozygote for the substitution c.256-1G>T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the pathogenic mutation c.1183C>T(p.Arg395Cys).
Myriad Women's Health, Inc. RCV000004477 SCV001194001 pathogenic Cholestanol storage disease 2019-12-26 criteria provided, single submitter clinical testing NM_000784.3(CYP27A1):c.1183C>T(R395C) is classified as pathogenic in the context of cerebrotendinous xanthomatosis. Sources cited for classification include the following: PMID 2019602, 10775536, 21955034 and 21645175. Classification of NM_000784.3(CYP27A1):c.1183C>T(R395C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000004477 SCV000024650 pathogenic Cholestanol storage disease 1991-04-25 no assertion criteria provided literature only
GeneReviews RCV000004477 SCV000087137 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Myriad Women's Health, Inc. RCV000004477 SCV000788833 pathogenic Cholestanol storage disease 2017-01-09 no assertion criteria provided clinical testing

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