rs144701596

chr2-218814972-G-Achr2-218814972-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000784.4(CYP27A1):c.1538G>A(p.Arg513His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,461,862 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R513C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000044 (1 hom.)
• Consequence: CYP27A1 NM_000784.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 8.28

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-218814971-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557779.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27A1	NM_000784.4	c.1538G>A	p.Arg513His	missense_variant	9/9	ENST00000258415.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27A1	ENST00000258415.9	c.1538G>A	p.Arg513His	missense_variant	9/9	1	NM_000784.4	P1
CYP27A1	ENST00000494263.5	n.2250G>A		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251482 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135914

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461862 Hom.: 1 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cholestanol storage disease Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 15, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 14, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 513 of the CYP27A1 protein (p.Arg513His). This variant is present in population databases (rs144701596, gnomAD 0.03%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 22878431). ClinVar contains an entry for this variant (Variation ID: 449362). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg513 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28623566, 31743419, 32714376). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22878431, 26153518, 28324197, 28623566) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.0075	T
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.66
MVP		0.91
MPC		0.77
ClinPred		0.53	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs144701596; hg19: chr2-219679695;