rs864622666

chr9-127825740-TGGCC-T

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.640_643del(p.Gly214ThrfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G214G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.36

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 9-127825740-TGGCC-T is Pathogenic according to our data. Variant chr9-127825740-TGGCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 220826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127825740-TGGCC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.640_643del	p.Gly214ThrfsTer7	frameshift_variant	5/15	ENST00000373203.9
ENG	NM_000118.4	c.640_643del	p.Gly214ThrfsTer7	frameshift_variant	5/14
ENG	NM_001278138.2	c.94_97del	p.Gly32ThrfsTer7	frameshift_variant	5/15
ENG	NM_001406715.1	c.640_643del	p.Gly214ThrfsTer7	frameshift_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.640_643del	p.Gly214ThrfsTer7	frameshift_variant	5/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.640_643del	p.Gly214ThrfsTer7	frameshift_variant	5/14	1		A2
ENG	ENST00000480266.6	c.94_97del	p.Gly32ThrfsTer7	frameshift_variant	5/15	2
ENG	ENST00000462196.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2015	This sequence change deletes 4 nucleotides from exon 5 of the ENG mRNA (c.640_643delGGCC), causing a frameshift at codon 214. This creates a premature translational stop signal (p.Gly214Thrfs*7) and is expected to result in an absent or disrupted protein product. Truncating variants in ENG are known to be pathogenic (PMID: 21158752, 12673790). This particular deletion has been reported in individuals affected with hereditary hemorrhagic telangiectasia (PMID: 15266205, 16752392). This variant is also known as c.635_638delGGCC in the literature. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 19, 2018	The ENG c.640_643delGGCC p.(Gly214ThrfsTer7) variant, also referred to as c.635_638delGGCC or p.(Gly214fsTer220), causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. The c.640_643delGGCC variant has been reported in two studies in which it is found in a heterozygous state in two individuals with hereditary hemorrhagic telangiectasia (Bayrak-Toydemir et al. 2004; Bossler et al. 2006). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Based on the available evidence, the c.640_643delGGCC p.(Gly214ThrfsTer7) variant is classified as pathogenic for hereditary hemorrhagic telangiectasia. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 04, 2023

PM2_supporting, PS4_supporting, PVS1 -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2023

This sequence change creates a premature translational stop signal (p.Gly214Thrfs*7) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15266205, 16752392). This variant is also known as c.635_638delGGCC or c.640_644delGGCC. ClinVar contains an entry for this variant (Variation ID: 220826). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2023

The c.640_643delGGCC pathogenic mutation, located in coding exon 5 of the ENG gene, results from a deletion of 4 nucleotides at nucleotide positions 640 to 643, causing a translational frameshift with a predicted alternate stop codon (p.G214Tfs*7). This pathogenic alteration, designated as c.635_638delGGCC, was described in an individual with epistaxis, telangiectasias, and family history of hereditary hemorrhagic telangiectasia (HHT) (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75). Another study also identified this mutation, designated as c.640_644delGGCC, in an individual with HHT (Bayrak-Toydemir P et al. Am. J. Med. Genet. A, 2006 Mar;140:463-70). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs864622666; hg19: chr9-130588019;