rs1064794219

Positions:

• chr9-127825321-GCAGCT-G

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.721_725del​(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 (★★). 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:5
• Conservation: PhyloP100: 3.31

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 9-127825321-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/exons	MANE	UniProt
ENG	NM_001114753.3	c.721_725del	p.Ser241ArgfsTer91	frameshift_variant	6/15	ENST00000373203.9
ENG	NM_000118.4	c.721_725del	p.Ser241ArgfsTer91	frameshift_variant	6/14
ENG	NM_001278138.2	c.175_179del	p.Ser59ArgfsTer91	frameshift_variant	6/15
ENG	NM_001406715.1	c.721_725del	p.Ser241ArgfsTer91	frameshift_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.721_725del	p.Ser241ArgfsTer91	frameshift_variant	6/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.721_725del	p.Ser241ArgfsTer91	frameshift_variant	6/14	1		A2
ENG	ENST00000480266.6	c.175_179del	p.Ser59ArgfsTer91	frameshift_variant	6/15	2

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: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	Fulgent Genetics, Fulgent Genetics	May 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 23, 2019	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:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2021

Not observed in large population cohorts (Lek et al., 2016); 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; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 419981; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21158752, 20414677) -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2018

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). 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064794219; hg19: chr9-130587600;