2-218814186-C-A

Position:

• chr2-218814186-C-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_000784.4(CYP27A1):​c.1183C>A​(p.Arg395Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R395C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CYP27A1 NM_000784.4 missense, splice_region
• Scores: Splicing: ADA: 0.9744
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 1.02

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-218814186-C-T is described in Lovd as [Pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-218814186-C-A is Pathogenic according to our data. Variant chr2-218814186-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.1183C>A	p.Arg395Ser	missense_variant, splice_region_variant	6/9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9	c.1183C>A	p.Arg395Ser	missense_variant, splice_region_variant	6/9	1	NM_000784.4	ENSP00000258415	P1
CYP27A1	ENST00000494263.5	n.1617C>A		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251236 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cholestanol storage disease Pathogenic:5 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 27, 1998	- -
Uncertain significance, flagged submission	clinical testing	Counsyl	Sep 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	Variant summary: CYP27A1 c.1183C>A (p.Arg395Ser) 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, one publication reports experimental evidence that this variant affects mRNA splicing and is expected to lead to the loss of protein expression (Chen_1998). The variant allele was found at a frequency of 8e-06 in 251236 control chromosomes. c.1183C>A has been reported in the literature in individuals affected with Cerebrotendinous Xanthomatosis and clinical frontotemporal dementia (Chen_1998, Blauwendraat_2018). Additionally, the demonstrated alternative pre-mRNA splicing was shown to lead to decreased sterol 27-hydroxylase activity (Chen_1998). Other variants at the same codon have been widely reported to be pathogenic (p.Arg395Cys, p.Arg395His). ClinVar contains an entry for this variant (Variation ID: 4261). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2023	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 395 of the CYP27A1 protein (p.Arg395Ser). This variant is present in population databases (rs121908096, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of cerebrotendinous xanthomatosis (PMID: 9790667, 28749476). This variant is also known as p.Arg362Ser. ClinVar contains an entry for this variant (Variation ID: 4261). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 9790667). This variant disrupts the p.Arg395 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2019602, 20402754, 26156051). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.98		Loss of methylation at R395 (P = 0.0885);
MVP		0.99
MPC		0.76
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.0		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: rs121908096; hg19: chr2-219678909; COSMIC: COSV99033441; COSMIC: COSV99033441;