Submissions for variant NM_000784.4(CYP27A1):c.784C>T (p.Arg262Cys)

gnomAD frequency: 0.00015  dbSNP: rs778371330

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001866266	SCV002200953	uncertain significance	Cholestanol storage disease	2025-01-14	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 262 of the CYP27A1 protein (p.Arg262Cys). This variant is present in population databases (rs778371330, gnomAD 0.02%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 32581172). ClinVar contains an entry for this variant (Variation ID: 1284558). 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) has been performed 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004039951	SCV003561766	uncertain significance	Cardiovascular phenotype	2021-07-08	criteria provided, single submitter	clinical testing	The c.784C>T (p.R262C) alteration is located in exon 4 (coding exon 4) of the CYP27A1 gene. This alteration results from a C to T substitution at nucleotide position 784, causing the arginine (R) at amino acid position 262 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001699978	SCV005889037	uncertain significance	not provided	2024-09-11	criteria provided, single submitter	clinical testing	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: 32581172, Hanson2024[preprint])
Clinical Genetics, Academic Medical Center	RCV001699978	SCV001917177	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001699978	SCV001966010	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003394217	SCV004119036	uncertain significance	CYP27A1-related disorder	2024-08-21	no assertion criteria provided	clinical testing	The CYP27A1 c.784C>T variant is predicted to result in the amino acid substitution p.Arg262Cys. This variant was reported in the compound heterozygous state in an individual with late on-set cerebrotendinous xanthomatosis (Takasone et al. 2020. PubMed ID: 32581172). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.