Submissions for variant NM_000784.4(CYP27A1):c.1436G>A (p.Arg479His)

dbSNP: rs199638075

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000596853	SCV000702838	uncertain significance	not provided	2017-12-14	criteria provided, single submitter	clinical testing
Invitae	RCV001243512	SCV001416679	likely pathogenic	Cholestanol storage disease	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 479 of the CYP27A1 protein (p.Arg479His). This variant is present in population databases (rs199638075, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CYP27A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 498030). 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. Experimental studies have shown that this missense change affects CYP27A1 function (PMID: 34930075). This variant disrupts the p.Arg479 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2019602, 21073839, 24584636). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003420030	SCV004113260	likely pathogenic	CYP27A1-related condition	2023-07-24	criteria provided, single submitter	clinical testing	The CYP27A1 c.1436G>A variant is predicted to result in the amino acid substitution p.Arg479His. The variant was reported in the heterozygous state in an individual with intrahepatic cholestasis of pregnancy (Xin et al. 2021. PubMed ID: 34930075). At PreventionGenetics, this variant was found in two patients tested for cerebrotendinous xanthomatosis (CTX) (Internal Data). The first patient was homozygous for this variant and parental testing confirmed that both parents were heterozygous carriers. The second patient was found to have this variant in the heterozygous state along with a second pathogenic variant in CYP27A1; however, parental testing was not completed to confirm the phase of these variants. This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219679440-G-A). Of note, several different variants that affect this same amino acid residue (p.Arg479Gly, p.Arg479Ser, p.Arg479Cys) have been reported in individuals with CTX (Guyant-Maréchal et al. 2005. PubMed ID: 16278884; Jiao et al. 2018. PubMed ID: 29095540; Mandrile et al. 2014. PubMed ID: 24584636). Based on this evidence we interpret the c.1436G>A (p.Arg479His) variant as likely pathogenic.
Natera, Inc.	RCV001243512	SCV002078810	uncertain significance	Cholestanol storage disease	2020-03-30	no assertion criteria provided	clinical testing