Total submissions: 11
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, |
RCV001267948 | SCV001446470 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Gene |
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) |
Ce |
RCV001267948 | SCV002496638 | pathogenic | not provided | 2022-02-01 | criteria provided, single submitter | clinical testing | |
Laboratorio de Genetica e Diagnostico Molecular, |
RCV002251956 | SCV002523876 | pathogenic | See cases | 2020-11-27 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PS4, PM2, PM3 |
Fulgent Genetics, |
RCV000056110 | SCV002810277 | pathogenic | Cholestanol storage disease | 2022-02-14 | criteria provided, single submitter | clinical testing | |
Prevention |
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 | |
Gene |
RCV000056110 | SCV000087187 | pathologic | Cholestanol storage disease | 2013-08-01 | no assertion criteria provided | curation | Converted during submission to Pathogenic. |
Natera, |
RCV000056110 | SCV002078763 | pathogenic | Cholestanol storage disease | 2020-09-17 | no assertion criteria provided | clinical testing |