rs121908099

chr2-218814409-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000784.4(CYP27A1):c.1214G>A(p.Arg405Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R405W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CYP27A1 NM_000784.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1
• Conservation: PhyloP100: 6.70

Genes affected

CYP27A1 (HGNC:2605): (cytochrome P450 family 27 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Since the conversion of cholesterol to bile acids is the major route for removing cholesterol from the body, this protein is important for overall cholesterol homeostasis. Mutations in this gene cause cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000784.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-218814408-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 65838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 2-218814409-G-A is Pathogenic according to our data. Variant chr2-218814409-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218814409-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27A1	NM_000784.4	c.1214G>A	p.Arg405Gln	missense_variant	7/9	ENST00000258415.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27A1	ENST00000258415.9	c.1214G>A	p.Arg405Gln	missense_variant	7/9	1	NM_000784.4	P1
CYP27A1	ENST00000494263.5	n.1840G>A		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251480 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74472

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cholestanol storage disease Pathogenic:11

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 15, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	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). 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: 9186905). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 25, 2023	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. -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 16, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2017	- -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.96
MPC		0.77
ClinPred		0.95	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.92
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908099; hg19: chr2-219679132;