ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.379C>T (p.Arg127Trp)

gnomAD frequency: 0.00010  dbSNP: rs201114717
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000056110 SCV000788802 likely pathogenic Cholestanol storage disease 2016-12-21 criteria provided, single submitter clinical testing
Invitae RCV000056110 SCV000933713 pathogenic Cholestanol storage disease 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 127 of the CYP27A1 protein (p.Arg127Trp). This variant is present in population databases (rs201114717, gnomAD 0.02%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 10430841, 10775536, 17319284, 23659550, 27455001, 28623566). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg94Trp. ClinVar contains an entry for this variant (Variation ID: 65865). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP27A1 protein function. This variant disrupts the p.Arg127 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8730343, 10775536; Invitae). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001267948 SCV001446470 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
GeneDx RCV001267948 SCV001823953 pathogenic not provided 2022-06-29 criteria provided, single submitter clinical testing In vitro functional studies suggest disrupted protein expression and heme binding (Sawada et al., 2001; Gupta et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21604088, 31796091, 30778698, 17697869, 24836315, 11181744, 23659550, 16816916, 27455001, 10430841, 28937538, 28623566, 26643207, 26550830, 32714376, 31980526, 33414089, 32344004, 32531740, 34426522, 31589614, 11737215)
CeGaT Center for Human Genetics Tuebingen RCV001267948 SCV002496638 pathogenic not provided 2022-02-01 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251956 SCV002523876 pathogenic See cases 2020-11-27 criteria provided, single submitter clinical testing ACMG classification criteria: PS4, PM2, PM3
Fulgent Genetics, Fulgent Genetics RCV000056110 SCV002810277 pathogenic Cholestanol storage disease 2022-02-14 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003415826 SCV004118437 pathogenic CYP27A1-related condition 2022-12-28 criteria provided, single submitter clinical testing The CYP27A1 c.379C>T variant is predicted to result in the amino acid substitution p.Arg127Trp. This variant is alternatively referred to as p.Arg94Trp in the literature. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with cerebrotendinous xanthomatosis (Verrips et al. 1999. PubMed ID: 10430841, Table 2; Kapás et al. 2014. PubMed ID: 23659550; Zhang et al. 2016. PubMed ID: 27455001; Chen et al. 2017. PubMed ID: 28623566, Table 3; Gong et al. 2017. PubMed ID: 28937538, Table 2; Elert-Dobkowska et al. 2019. PubMed ID: 30778698, Tables 1 and 2; Jiang et al. 2020. PubMed ID: 32714376). In some of these individuals, the disorder was reported to manifest as neonatal cholestasis (Gong et al. 2017. PubMed ID: 28937538, Table 2). Functional studies suggest this variant may impact heme activity (Gupta et al. 2007. PubMed ID: 17697869, data not shown). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219674423-C-T). In ClinVar, this variant is interpreted as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/65865/). This variant is interpreted as pathogenic.
Baylor Genetics RCV000056110 SCV004192648 pathogenic Cholestanol storage disease 2023-10-20 criteria provided, single submitter clinical testing
GeneReviews RCV000056110 SCV000087187 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000056110 SCV002078763 pathogenic Cholestanol storage disease 2020-09-17 no assertion criteria provided clinical testing

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