rs1554810490

chr9-127826522-G-A

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.511C>T(p.Arg171Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R171R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.76

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 9-127826522-G-A is Pathogenic according to our data. Variant chr9-127826522-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 439644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127826522-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.511C>T	p.Arg171Ter	stop_gained	4/15	ENST00000373203.9
ENG	NM_000118.4	c.511C>T	p.Arg171Ter	stop_gained	4/14
ENG	NM_001406715.1	c.511C>T	p.Arg171Ter	stop_gained	4/8
ENG	NM_001278138.2	c.-36C>T		5_prime_UTR_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.511C>T	p.Arg171Ter	stop_gained	4/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.511C>T	p.Arg171Ter	stop_gained	4/14	1		A2
ENG	ENST00000480266.6	c.-36C>T		5_prime_UTR_variant	4/15	2
ENG	ENST00000462196.1	n.411C>T		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 25, 2022	- -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PVS1+PM2+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000439644.5, PMID: 15375013). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2021	Not observed in large population cohorts (Lek et al., 2016); Nonsense 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; Published functional studies demonstrate that the variant results in premature mRNA degradation (Shovlin et al., 1997) and diminishes endoglin up-regulation in activated monocytes (Sanz-Rodriguez et al., 2004); Reported in ClinVar as pathogenic (ClinVar Variant ID# 439644; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 16752392, 15024723, 12920067, 16470787, 16429404, 21415079, 16470589, 12786761, 15993872, 9245986, 15375013, 25525159, 32300199, 15849752) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 11, 2018	The ENG c.511C>T; p.Arg171Ter variant is reported in the literature in individuals and families affected with hereditary hemorrhagic telangiectasia (Berg 2003, Goldschmidt 2005, Lastella 2003, Lesca 2004, Sanz-Rodriguez 2004, Shovlin 1997). This variant is reported as pathogenic in ClinVar (Variation ID: 439644) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In vitro functional analyses demonstrate diminished upregulation of endoglin during monocyte activation (Sanz-Rodriguez 2004). Based on the above information, this variant is considered pathogenic. References: Berg J et al. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations. J Med Genet. 2003 Aug;40(8):585-90. Goldschmidt N et al. Association of hereditary hemorrhagic telangiectasia and hereditary nonpolyposis colorectal cancer in the same kindred. Int J Cancer. 2005 Sep 20;116(5):808-12. Lastella P et al. Endoglin gene mutations and polymorphisms in Italian patients with hereditary haemorrhagic telangiectasia. Clin Genet. 2003 Jun;63(6):536-40. Lesca G et al. Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Hum Mutat. 2004 Apr;23(4):289-99. Sanz-Rodriguez F et al. Mutation analysis in Spanish patients with hereditary hemorrhagic telangiectasia: deficient endoglin up-regulation in activated monocytes. Clin Chem. 2004 Nov;50(11):2003-11. Shovlin C et al. Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am J Hum Genet. 1997 Jul;61(1):68-79. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2022

The p.R171* pathogenic mutation (also known as c.511C>T), located in coding exon 4 of the ENG gene, results from a C to T substitution at nucleotide position 511. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation was identified in multiple individuals with hereditary hemorrhagic telangiectasia (Lastella P et al. Clin. Genet., 2003 Jun;63:536-40; Lesca G et al. Hum. Mutat., 2004 Apr;23:289-99; Goldschmidt N et al. Int. J. Cancer, 2005 Sep;116:808-12; Lenato GM et al. Hum. Mutat., 2006 Feb;27:213-4; Bayrak-Toydemir P et al. Am. J. Med. Genet. A, 2006 Mar;140:463-70; Lee NP et al. J. Med. Genet., 2011 May;48:353-7), including one family in which analysis of cultured peripheral blood mononuclear cells derived from two affected individuals showed significantly decreased upregulation of the ENG gene compared to an unaffected relative (Sanz-Rodriguez F et al. Clin Chem. 2004;50(11):2003-2011). 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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2023

This sequence change creates a premature translational stop signal (p.Arg171*) 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: 9245986, 12920067, 15024723, 15375013, 15849752). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 439644). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.84
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1554810490; hg19: chr9-130588801; COSMIC: COSV61227618; COSMIC: COSV61227618;