rs863223532

Positions:

• chr9-127829800-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.247C>T​(p.Gln83Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.779

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127829800-G-A is Pathogenic according to our data. Variant chr9-127829800-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 213205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127829800-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.247C>T	p.Gln83Ter	stop_gained	3/15	ENST00000373203.9
ENG	NM_000118.4	c.247C>T	p.Gln83Ter	stop_gained	3/14
ENG	NM_001406715.1	c.247C>T	p.Gln83Ter	stop_gained	3/8
ENG	NM_001278138.2	c.-300C>T		5_prime_UTR_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.247C>T	p.Gln83Ter	stop_gained	3/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.247C>T	p.Gln83Ter	stop_gained	3/14	1		A2
ENG	ENST00000480266.6	c.-300C>T		5_prime_UTR_variant	3/15	2
ENG	ENST00000462196.1	n.5C>T		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 21, 2018	The p.Gln83Ter variant (rs863223532) was reported in three probands with HHT, where one of the families was shown segregation of the variant with disease (Letteboer 2005). It is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), the Genome Aggregation Database (gnomAD), and has been reported to the ClinVar database with a pathogenic classification (Variation ID: 213205). The c.247C>T variant creates a premature termination codon in exon 3 (of 14 exons) in the ENG gene, which results in a truncated protein product or mRNA subject to non-sense mediated decay. Based on the above information, this variant is considered to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2014	p.Gln83Ter (CAG>TAG): c.247 C>T in exon 3 of the ENG gene (NM_000118.2)The Q83X mutation in the ENG gene has been reported in three Dutch probands meeting the clinical criteria for HHT (Letteboer et al., 2005). The Q83X mutation was found to segregate with the HHT phenotype in at least one of the three families. Additionally, Q83X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the ENG gene have been reported in association with HHT. Furthermore, the Q83X mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Q83X in the ENG gene is interpreted as a disease-causing mutation. This variant was found in HHT-ARRHYTHMIA -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2017

The p.Q83* pathogenic mutation (also known as c.247C>T), located in coding exon 3 of the ENG gene, results from a C to T substitution at nucleotide position 247. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation was identified in 3 hereditary hemorrhagic telangiectasia families (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 213205). This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15517393). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln83*) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.21	N
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.84
GERP RS		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs863223532; hg19: chr9-130592079;