rs1064794219

Variant names:

• chr9-127825321-GCAGCT-G
• rs1064794219
• NM_001114753.3:c.721_725delAGCTG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.721_725delAGCTG​(p.Ser241ArgfsTer91) 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. S241S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 26)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.31
• Publications: 0 publications found

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]

ENG Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 9-127825321-GCAGCT-G is Pathogenic according to our data. Variant chr9-127825321-GCAGCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 419981.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.721_725delAGCTG	p.Ser241ArgfsTer91	frameshift_variant	Exon 6 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.721_725delAGCTG	p.Ser241ArgfsTer91	frameshift_variant	Exon 6 of 14		NP_000109.1
ENG	NM_001278138.2	c.175_179delAGCTG	p.Ser59ArgfsTer91	frameshift_variant	Exon 6 of 15		NP_001265067.1
ENG	NM_001406715.1	c.721_725delAGCTG	p.Ser241ArgfsTer91	frameshift_variant	Exon 6 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.721_725delAGCTG	p.Ser241ArgfsTer91	frameshift_variant	Exon 6 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 26

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

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

May 30, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ENG c.721_725delAGCTG; p.Ser241fs variant (rs1064794219) is reported in individuals with HHT (McDonald 2011, Richards-Yutz 2010), and is classified as pathogenic in ClinVar (Variation ID: 419981). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting five nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. Richards-Yutz J et al. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet. 2010 Jul;128(1):61-77. -

not provided Pathogenic:2

Mar 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with HHT referred for genetic testing at GeneDx and in published literature (PMID: 20414677, 21158752); Not observed in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21158752, 20414677) -

Sep 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PS4_moderate, PVS1 -

ENG-related disorder Pathogenic:1

May 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ENG c.721_725del5 variant is predicted to result in a frameshift and premature protein termination (p.Ser241Argfs*91). This variant has been reported in individuals with hereditary haemorrhagic telangiectasia (Table 3, Richards-Yutz et al. 2010. PubMed ID: 20414677; Supplementary Table 1, McDonald et al. 2011. PubMed ID: 21158752; Internal Data, PreventionGenetics). 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. -

Cardiovascular phenotype Pathogenic:1

Dec 20, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.721_725delAGCTG pathogenic mutation, located in coding exon 6 of the ENG gene, results from a deletion of 5 nucleotides at nucleotide positions 721 to 725, causing a translational frameshift with a predicted alternate stop codon (p.S241Rfs*91). This mutation has been reported in an individual with hereditary hemorrhagic telangiectasia presenting with epistaxis, telangiectasias, cerebral arteriovenous malformation, and a positive family history (McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). 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. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser241Argfs*91) 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 hemorraghic telangiectasia (PMID: 20414677, 21158752). ClinVar contains an entry for this variant (Variation ID: 419981). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1064794219; hg19: chr9-130587600;