Submissions for variant NM_000784.4(CYP27A1):c.1214G>A (p.Arg405Gln)

gnomAD frequency: 0.00001  dbSNP: rs121908099

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000004482	SCV000267284	likely pathogenic	Cholestanol storage disease	2016-03-18	criteria provided, single submitter	reference population
Eurofins Ntd Llc (ga)	RCV000726759	SCV000702839	pathogenic	not provided	2017-12-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004482	SCV000712211	pathogenic	Cholestanol storage disease	2016-06-15	criteria provided, single submitter	clinical testing	The p.Arg405Gln variant in CYP27A1 has been reported in at least 3 families (1 h omozygous and 2 compound heterozygous) with cerebrotendinous xanthomatosis and s egregated with disease in 3 affected relatives from 2 families (Chen 1997, Suh 2 011). It has also been reported, in the compound heterozygous state, in 2 patie nts with the spinal form of the disease (Abe 2015, Yanagihashi 2016). . In vitr o functional studies provide some evidence that the p.Arg405Gln variant may impa ct protein function (Chen 1997). This variant has been identified in 8/121,382 o f chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs121908099). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrie r frequency. In summary, this variant meets our criteria to be classified as pat hogenic for cerebrotendinous xanthomatosis in an autosomal recessive manner, bas ed upon case observations, segregation studies, low frequency in controls and fu nctional evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004482	SCV000954777	pathogenic	Cholestanol storage disease	2024-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 405 of the CYP27A1 protein (p.Arg405Gln). This variant is present in population databases (rs121908099, gnomAD 0.04%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 9186905, 14741198, 21958693, 25447658, 25941960, 26861945, 28623566, 29321515). 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: 4260). 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%. Experimental studies have shown that this missense change affects CYP27A1 function (PMID: 9186905). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000004482	SCV001162938	pathogenic	Cholestanol storage disease	2024-03-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000726759	SCV001773376	pathogenic	not provided	2023-10-25	criteria provided, single submitter	clinical testing	Observed in 0.004% (10/251480) alleles in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25447658, 9186905, 25941960, 26861945, 30609409, 28937538, 16816916, 29321515, 21958693, 28623566, 33414089, 31589614, 32523054, 35578252, 14741198)
Fulgent Genetics, Fulgent Genetics	RCV000004482	SCV002797535	pathogenic	Cholestanol storage disease	2024-04-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000004482	SCV003819428	pathogenic	Cholestanol storage disease	2022-05-12	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000004482	SCV003841345	pathogenic	Cholestanol storage disease	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.42). Same nucleotide change resulting in same amino acid change and a different missense change at the same codon (p.Arg405Trp / ClinVar ID: VCV000065838) have been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004260). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 32523054). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004482	SCV004028812	pathogenic	Cholestanol storage disease	2023-07-25	criteria provided, single submitter	clinical testing	Variant summary: CYP27A1 c.1214G>A (p.Arg405Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251480 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CYP27A1 causing Cerebrotendinous Xanthomatosis (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.1214G>A has been reported in the literature in multiple individuals affected with Cerebrotendinous Xanthomatosis as a homozygous and compound heterozygous genotype (e.g. Chen_1997, Hong_2020, Zhang_2021) often presenting in infancy. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal CTX sterol 27-hydroxylase activity in vitro (e.g. Chen_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9186905, 32523054, 33414089). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=8), likely pathogenic (n=2), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004482	SCV000024655	pathogenic	Cholestanol storage disease	1997-05-01	no assertion criteria provided	literature only
Counsyl	RCV000004482	SCV000789751	likely pathogenic	Cholestanol storage disease	2017-02-16	no assertion criteria provided	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252459	SCV001428215	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000004482	SCV001459898	pathogenic	Cholestanol storage disease	2020-09-16	no assertion criteria provided	clinical testing