Submissions for variant NM_000784.4(CYP27A1):c.1537C>T (p.Arg513Cys)

gnomAD frequency: 0.00001  dbSNP: rs560108684

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000673959	SCV000960676	pathogenic	Cholestanol storage disease	2024-12-19	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 513 of the CYP27A1 protein (p.Arg513Cys). This variant is present in population databases (rs560108684, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of CYP27A1-related conditions (PMID: 28623566, 31743419, 32714376, 34012265). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 557779). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CYP27A1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg513 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been observed in individuals with CYP27A1-related conditions (PMID: 22878431), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000673959	SCV002511566	likely pathogenic	Cholestanol storage disease	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: CYP27A1 c.1537C>T (p.Arg513Cys) 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 5.2e-05 in 251486 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CYP27A1 causing Cerebrotendinous Xanthomatosis (5.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.1537C>T has been reported in the literature in the compound heterozygous state in individuals affected with Cerebrotendinous Xanthomatosis, including two individuals from a single family (Chen_2017, Jiang_2020, Zhang_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000673959	SCV004192654	pathogenic	Cholestanol storage disease	2024-03-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000673959	SCV005647761	likely pathogenic	Cholestanol storage disease	2024-01-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000673959	SCV000799222	uncertain significance	Cholestanol storage disease	2018-04-11	flagged submission	clinical testing
Natera, Inc.	RCV000673959	SCV001459903	uncertain significance	Cholestanol storage disease	2020-09-16	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748897	SCV005353852	uncertain significance	CYP27A1-related disorder	2024-07-31	no assertion criteria provided	clinical testing	The CYP27A1 c.1537C>T variant is predicted to result in the amino acid substitution p.Arg513Cys. This variant has been reported in the compound heterozygous state in individuals with cerebrotendinous xanthomatosis (Chen et al. 2017. PubMed ID: 28623566; Jiang et al. 2020. PubMed ID: 32714376). This variant is reported in 0.029% of alleles in individuals of South Asian descent in gnomAD. This variant has interpretations ranging from uncertain significance to pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/557779/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.