rs1554810215

Positions:

• chr9-127825239-G-A

Variant summary

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

The ENST00000373203.9(ENG):​c.808C>T​(p.Gln270Ter) 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: 27)
• Consequence: ENG ENST00000373203.9 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.87

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 9-127825239-G-A is Pathogenic according to our data. Variant chr9-127825239-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 458355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127825239-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.808C>T	p.Gln270Ter	stop_gained	6/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.808C>T	p.Gln270Ter	stop_gained	6/14		NP_000109.1
ENG	NM_001278138.2	c.262C>T	p.Gln88Ter	stop_gained	6/15		NP_001265067.1
ENG	NM_001406715.1	c.808C>T	p.Gln270Ter	stop_gained	6/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.808C>T	p.Gln270Ter	stop_gained	6/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.808C>T	p.Gln270Ter	stop_gained	6/14	1		ENSP00000341917	A2
ENG	ENST00000480266.6	c.262C>T	p.Gln88Ter	stop_gained	6/15	2		ENSP00000479015

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 27

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hereditary haemorrhagic telangiectasia type 1 (HHT; MIM#187300). Multiple pathogenic null variants have been reported, and missense variants have been demonstrated to have both loss of function and dominant negative effects on protein activity (PMIDs: 25080347, 25312062). (I). 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are multiple likely pathogenic and pathogenic NMD-predicted variants that have been reported (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five individuals or families with hereditary haemorrhagic telangiectasia (ClinVar, PMIDs: 24001356, 29483005, 31455059). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Dec 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 10, 2022	- -

Hereditary hemorrhagic telangiectasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2017	This sequence change creates a premature translational stop signal (p.Gln270*) in the ENG gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hemorrhagic telangiectasia in a family (PMID: 24001356). Loss-of-function variants in ENG are known to be pathogenic (PMID: 21158752, 12673790). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change in ENG is a nonsense variant predicted to cause a premature stop codon, p.(Gln270*), in biologically relevant exon 6/15 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 20301525). This variant is absent from population database gnomAD v2.1 and v3.1. This variant has been reported in at least three probands with a clinical diagnosis of hereditary haemorrhagic telangiectasia and segregates with disease (PMID: 24001356, 31455059, 32300199). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4_Moderate, PM2_Supporting, PP1. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 19, 2018

The ENG c.808C>T; p.Gln270Ter variant is reported in the literature in a family affected with HHT (Torring 2014). This variant is also reported as pathogenic in ClinVar (Variation ID: 458355), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA that is subject to nonsense medicated decay. Based on the above information, this variant is considered pathogenic. REFERENCES Torring PM et al. National mutation study among Danish patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2014 Aug;86(2):123-33. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.83	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.80
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1554810215; hg19: chr9-130587518;