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

gnomAD frequency: 0.00031  dbSNP: rs121908096

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000275162	SCV000329815	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; specifically, in vitro functional studies showed no detectable enzyme activity in cells transfected with R362C cDNA (Cali et al., 1991); Known as R362C according to alternate nomenclature; This variant is associated with the following publications: (PMID: 17697869, 10775536, 10430841, 26906304, 25983621, 12933951, 20402754, no PMID, 2019602, 8931710, 11181744, 21645175, 26156051, 21955034, 24746394, 22849591, 18227423, 28894950, 29260356, 31859899, 31980526, 33659184, 34103343, 34426522, 31589614, 33977023)
Illumina Laboratory Services, 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.
Eurofins Ntd Llc (ga)	RCV000275162	SCV000700806	pathogenic	not provided	2018-06-21	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000004477	SCV000744173	likely pathogenic	Cholestanol storage disease	2017-12-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004477	SCV000754983	pathogenic	Cholestanol storage disease	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 395 of the CYP27A1 protein (p.Arg395Cys). This variant is present in population databases (rs121908096, gnomAD 0.05%). This missense change has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 2019602, 10775536, 18227423, 20402754, 21645175, 21955034, 24746394, 26156051, 26906304). This variant is also known as p.Arg362Cys. ClinVar contains an entry for this variant (Variation ID: 4255). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CYP27A1 function (PMID: 2019602). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg395 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8950197, 9790667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Genetics, 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000275162	SCV001447794	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004477	SCV001520838	pathogenic	Cholestanol storage disease	2024-03-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000004477	SCV002018129	pathogenic	Cholestanol storage disease	2023-09-05	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000004477	SCV002506658	pathogenic	Cholestanol storage disease	2021-04-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000004477	SCV002769446	pathogenic	Cholestanol storage disease	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cerebrotendinous xanthomatosis (MIM#213700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. This variant is also in a splice region (second last coding base of exon 6), however cDNA studies have shown it does not affect splicing (PMID: 25983621). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (80 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 14 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Cytochrome P450 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as pathogenic, in either a homozygous or compound heterozygous state, in multiple patients with cerebrotendinous xanthomatosis (ClinVar, PMIDs: 2019602, 21645175, 28324197). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in multiple families (PMIDs: 21645175, 28324197). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells displayed reduced enzyme activity (PMID: 2019602). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000004477	SCV003806874	pathogenic	Cholestanol storage disease	2022-07-12	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM3 strong, PP3 supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV000275162	SCV004226013	pathogenic	not provided	2023-05-12	criteria provided, single submitter	clinical testing	PP3, PM3_strong, PS3, PS4_moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004477	SCV005395024	pathogenic	Cholestanol storage disease	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: CYP27A1 c.1183C>T (p.Arg395Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251236 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CYP27A1 causing Cerebrotendinous Xanthomatosis (0.00029 vs 0.0011), allowing no conclusion about variant significance. c.1183C>T has been reported in the literature in multiple individuals affected with Cerebrotendinous Xanthomatosis (e.g. Degos_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27084087). ClinVar contains an entry for this variant (Variation ID: 4255). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004477	SCV000024650	pathogenic	Cholestanol storage disease	1991-04-25	no assertion criteria provided	literature only
GeneReviews	RCV000004477	SCV000087137	not provided	Cholestanol storage disease		no assertion provided	literature only	Founder variant in Israeli Druze [Falik-Zaccai et al 2008]
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252460	SCV001428216	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000004477	SCV001455786	pathogenic	Cholestanol storage disease	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000275162	SCV001740790	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000275162	SCV001919340	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000275162	SCV001955155	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000275162	SCV001965692	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003974793	SCV004798757	pathogenic	CYP27A1-related disorder	2024-09-20	no assertion criteria provided	clinical testing	The CYP27A1 c.1183C>T variant is predicted to result in the amino acid substitution p.Arg395Cys. This variant is located within the cytochrome P-450 domain of the protein and has been reported to be causative for autosomal recessive cerebrotendinous xanthomatosis (see for examples Cali et al. 1991. PubMed ID: 2019602 [reported as p.Arg362Cys]; Smalley et al. 2015. PubMed ID: 25983621; Huidekoper et al. 2016. PubMed ID: 26156051). The Cali et al. study also performed a functional assay using transfected mammalian cell cultures that showed the p.Arg395Cys substitution greatly reduced enzymatic activity of the protein (Cali et al. 1991. PubMed ID: 2019602). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. This variant has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/4255). Given all the evidence, we too interpret c.1183C>T (p.Arg395Cys) as pathogenic.