chr9-127825787-A-ACG

Position:

• chr9-127825787-A-ACG

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.595_596dupCG​(p.Thr200fs) 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 (★★). 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:3
• Conservation: PhyloP100: -1.77

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 9-127825787-A-ACG is Pathogenic according to our data. Variant chr9-127825787-A-ACG is described in ClinVar as [Pathogenic]. Clinvar id is 503943.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.595_596dupCG	p.Thr200fs	frameshift_variant	5/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.595_596dupCG	p.Thr200fs	frameshift_variant	5/14		NP_000109.1
ENG	NM_001278138.2	c.49_50dupCG	p.Thr18fs	frameshift_variant	5/15		NP_001265067.1
ENG	NM_001406715.1	c.595_596dupCG	p.Thr200fs	frameshift_variant	5/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.595_596dupCG	p.Thr200fs	frameshift_variant	5/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.595_596dupCG	p.Thr200fs	frameshift_variant	5/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.49_50dupCG	p.Thr18fs	frameshift_variant	5/15	2		ENSP00000479015.1
ENG	ENST00000462196.1	n.495_*1dupCG		downstream_gene_variant		3		ENSP00000519251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ENG-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2024

The ENG c.595_596dupCG variant is predicted to result in a frameshift and premature protein termination (p.Thr200Valfs*23). This variant was reported in individuals with hereditary hemorrhagic telangiectasia (HHT) (reported as c.596_597insCG in Bayrak-Toydemir et al. 2004. PubMed ID: 15266205; Table S1 in McDonald et al. 2020. PubMed ID: 32300199). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in ENG are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2017

The c.595_596dupCG pathogenic variant has been reported in association with HHT (Bayrak-Toydemir et al., 2004). This pathogenic variant causes a shift in reading frame starting at codon threonine 200, changing it to a valine, and creating a premature stop codon at position 23 of the new reading frame, denoted p.Thr200ValfsX23. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the ENG gene have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.595_596dupCG variant has not been observed in large population cohorts (Lek et al., 2016). -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15266205). This variant is also known as c.596_597insCG. ClinVar contains an entry for this variant (Variation ID: 503943). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr200Valfs*23) 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554810405; hg19: chr9-130588066;