9-127825770-C-G

Variant names:

• chr9-127825770-C-G
• NM_001114753.3:c.614G>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.614G>C​(p.Arg205Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.39

Genes affected

ENG (HGNC:3349): (endoglin) This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a region_of_interest OR1, C-terminal part (size 130) in uniprot entity EGLN_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127825770-C-G is Pathogenic according to our data. Variant chr9-127825770-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1751881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.614G>C	p.Arg205Pro	missense_variant	Exon 5 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.614G>C	p.Arg205Pro	missense_variant	Exon 5 of 14		NP_000109.1
ENG	NM_001278138.2	c.68G>C	p.Arg23Pro	missense_variant	Exon 5 of 15		NP_001265067.1
ENG	NM_001406715.1	c.614G>C	p.Arg205Pro	missense_variant	Exon 5 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.614G>C	p.Arg205Pro	missense_variant	Exon 5 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.614G>C	p.Arg205Pro	missense_variant	Exon 5 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.68G>C	p.Arg23Pro	missense_variant	Exon 5 of 15	2		ENSP00000479015.1
ENG	ENST00000462196.1	n.*19G>C		downstream_gene_variant		3		ENSP00000519251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Oct 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 205 of the ENG protein (p.Arg205Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary hemorrhagic telangiectasia (PMID: 20414677, 32300199, 34872578; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1751881). 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 ENG protein function. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Sep 10, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R205P variant (also known as c.614G>C), located in coding exon 5 of the ENG gene, results from a G to C substitution at nucleotide position 614. The arginine at codon 205 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected in individuals with definite hereditary hemorrhagic telangiectasia (HHT) based on diagnostic criteria, as well as in individuals with features of HHT where clinical details were limited (Ambry internal data; Gedge F et al, J Mol Diagn. 2007;9(2):258-265; Richards-Yutz J et al. Hum. Genet., 2010 Jul;128:61-77; McDonald J et al. Genet Med, 2020 07;22:1201-1205). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with HHT (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.4
DANN	Benign	0.96
DEOGEN2	Uncertain	0.53	D;T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N;.;N
REVEL	Benign	0.11
Sift	Benign	0.068	T;.;T
Sift4G	Benign	0.092	T;T;T
Polyphen		0.56	P;.;.
Vest4		0.62
MutPred		0.40		Loss of catalytic residue at R205 (P = 0.0028);.;Loss of catalytic residue at R205 (P = 0.0028);
MVP		0.62
MPC		0.71
ClinPred		0.29	T
GERP RS		-2.2
Varity_R		0.66
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130588049;