rs1554809513

Positions:

• chr9-127819937-C-T

Variant summary

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

The ENST00000373203.9(ENG):​c.1235G>A​(p.Cys412Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. C412G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG ENST00000373203.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.21

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in ENST00000373203.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-127819938-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1040195.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 9-127819937-C-T is Pathogenic according to our data. Variant chr9-127819937-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458332.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
ENG	NM_001114753.3	c.1235G>A	p.Cys412Tyr	missense_variant	9/15	ENST00000373203.9	NP_001108225.1
LOC102723566	NR_136302.1	n.1568+1226C>T		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1235G>A	p.Cys412Tyr	missense_variant	9/14		NP_000109.1
ENG	NM_001278138.2	c.689G>A	p.Cys230Tyr	missense_variant	9/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1235G>A	p.Cys412Tyr	missense_variant	9/15	1	NM_001114753.3	ENSP00000362299	P2
	ENST00000439298.5	n.1568+1226C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2015

The p.C412Y variant (also known as c.1235G>A), located in coding exon 9 of the ENG gene, results from a G to A substitution at nucleotide position 1235. The cysteine at codon 412 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was first reported in an individual with limited HHT features (Gedge F et al. J Mol Diagn. 2007;9(2):258-65). This alteration was also identified in a Japanese family with HHT (Komiyama M et al. J Hum Genet. 2014;59(1):37-41). In vitro studies showed that this alteration caused reduced cell surface presentation of the ENG protein and subsequently failed to enhance the ALK1 response to BMP9 compared to wild type (Mallet C et al, Hum. Mol. Genet. 2015 Feb; 24(4):1142-54). This variant has also been identified in our laboratory in two families with multiple family members affected with HHT carrying this alteration. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species on limited alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2023

This missense change has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 15024723, 17384219, 24196379, 25312062; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 412 of the ENG protein (p.Cys412Tyr). ClinVar contains an entry for this variant (Variation ID: 458332). 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) performed at Invitae indicates that this missense variant is expected to disrupt ENG protein function. Experimental studies have shown that this missense change affects ENG function (PMID: 25312062). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	0.70	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.9	D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.91
MutPred		0.91		Gain of disorder (P = 0.0775);.;Gain of disorder (P = 0.0775);
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.95
gMVP		1.0

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: rs1554809513; hg19: chr9-130582216;