2-218813095-C-T

Position:

chr2-218813095-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000784.4(CYP27A1):c.1016C>T(p.Thr339Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000653 in 1,608,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging 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. T339K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 missense, splice_region

Scores

Splicing: ADA: 0.9955

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 7.64

Variant links:

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]

CYP27A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 2-218813095-C-T is Pathogenic according to our data. Variant chr2-218813095-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218813095-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-218813095-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27A1	NM_000784.4 linkuse as main transcript	c.1016C>T	p.Thr339Met	missense_variant, splice_region_variant	5/9	ENST00000258415.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CYP27A1	ENST00000258415.9 linkuse as main transcript	c.1016C>T	p.Thr339Met	missense_variant, splice_region_variant	5/9	1	NM_000784.4	P1
CYP27A1	ENST00000466602.1 linkuse as main transcript	n.1138C>T		splice_region_variant, non_coding_transcript_exon_variant	2/3	2
CYP27A1	ENST00000494263.5 linkuse as main transcript	n.1450C>T		splice_region_variant, non_coding_transcript_exon_variant	5/7	2
CYP27A1	ENST00000445971.1 linkuse as main transcript	c.*477C>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	4/5	5

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000806

AC:

AN:

248042

Hom.:

AF XY:

0.0000744

AC XY:

AN XY:

134392

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000982

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000604

AC:

AN:

1456652

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

723764

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000622

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.000112

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000182

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cholestanol storage disease

Pathogenic:11

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CYP27A1 c.1016C>T (p.Thr339Met) variant has been reported in six studies in which it was found in a homozygous state in five individuals and in a compound heterozygous state in four individuals, all with cerebrotendinous xanthomatosis, and in a heterozygous state in four unaffected family members (Reshef et al. 1994; Guyant-Marechal et al. 2005; Pilo-de-la-Fuente et al. 2011; Caroppo et al. 2013; Schabhuttl et al. 2014; Huidekoper et al. 2016). The p.Thr339Met variant was absent from 100 controls and is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. The Thr306 residue is conserved and located in the heme-binding site of the protein. Based on the evidence, the p.Thr339Met variant is classified as pathogenic for cerebrotendinous xanthomatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 19, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 339 of the CYP27A1 protein (p.Thr339Met). This variant is present in population databases (rs121908102, gnomAD 0.01%). This missense change has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 8014582, 24627108, 26156051, 27858369). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr306Met. ClinVar contains an entry for this variant (Variation ID: 4266). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). 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: 0.94; 3Cnet: 0.74). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004266). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 24627108, 26156051, 27858369) and to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID:8014582). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1016C>T;p.(Thr339Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID 4266; PMID: 27142713; 26156051; 24627108; 23212406; 16278884) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11737215) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Cytochrome P450 domain) - PM1. The variant is present at low allele frequencies population databases (rs121908102– gnomAD 0.001117%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr339Met) was detected in trans with a pathogenic variant (PMID: 27142713; 26156051; 24627108; 23212406; 16278884) - PM3_very strong Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

not provided

Pathogenic:7

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 12, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2022	Published functional studies demonstrate absent functional heme activity (Gupta et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16278884, 26643207, 21404287, 17697869, 11181744, 26156051, 28894950, 30270055, 21627786, 21645175, 23212406, 24627108, 27142713, 27858369, 8014582, 31589614, 33414089, 31796091) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

CYP27A1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

The CYP27A1 c.1016C>T variant is predicted to result in the amino acid substitution p.Thr339Met. Using legacy nomenclature, this variant is also known in the literature as p.Thr306Met. This variant has been reported in several patients with cerebrotendinous xanthomatosis (Family #202 in Reshef et al 1994. PubMed ID: 8014582; Schabhüttl et al 2014. PubMed ID: 24627108; Guyant-Maréchal et al 2005. PubMed ID: 16278884; Huidekoper et al 2015. PubMed ID: 26156051). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and has been interpreted as pathogenic or likely pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4266). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

1.0

MutPred

0.95

Loss of phosphorylation at T339 (P = 0.0464);

MVP

0.96

MPC

0.73

ClinPred

0.98

GERP RS

5.4

Varity_R

0.88

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over