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NM_001114753.3(ENG):c.1510G>A (p.Val504Met) AND Telangiectasia, hereditary hemorrhagic, type 1

Germline classification:
Likely benign (3 submissions)
Last evaluated:
Mar 15, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000273165.17

Allele description [Variation Report for NM_001114753.3(ENG):c.1510G>A (p.Val504Met)]

NM_001114753.3(ENG):c.1510G>A (p.Val504Met)

Genes:
ENG:endoglin [Gene - OMIM - HGNC]
LOC102723566:uncharacterized LOC102723566 [Gene]
Variant type:
single nucleotide variant
Cytogenetic location:
9q34.11
Genomic location:
Preferred name:
NM_001114753.3(ENG):c.1510G>A (p.Val504Met)
Other names:
NM_001114753.3(ENG):c.1510G>A
HGVS:
  • NC_000009.12:g.127818296C>T
  • NG_009551.1:g.41473G>A
  • NM_000118.4:c.1510G>A
  • NM_001114753.3:c.1510G>AMANE SELECT
  • NM_001278138.2:c.964G>A
  • NP_000109.1:p.Val504Met
  • NP_000109.1:p.Val504Met
  • NP_001108225.1:p.Val504Met
  • NP_001108225.1:p.Val504Met
  • NP_001265067.1:p.Val322Met
  • LRG_589t1:c.1510G>A
  • LRG_589t2:c.1510G>A
  • LRG_589:g.41473G>A
  • LRG_589p1:p.Val504Met
  • LRG_589p2:p.Val504Met
  • NC_000009.11:g.130580575C>T
  • NM_000118.2:c.1510G>A
  • NM_000118.3:c.1510G>A
  • NM_001114753.1:c.1510G>A
  • NM_001114753.2:c.1510G>A
  • P17813:p.Val504Met
Protein change:
V322M
Links:
UniProtKB: P17813#VAR_026782; dbSNP: rs116330805
NCBI 1000 Genomes Browser:
rs116330805
Molecular consequence:
  • NM_000118.4:c.1510G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001114753.3:c.1510G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278138.2:c.964G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Telangiectasia, hereditary hemorrhagic, type 1 (HHT1)
Synonyms:
Osler Weber Rendu syndrome type 1
Identifiers:
MONDO: MONDO:0008535; MedGen: C4551861; Orphanet: 774; OMIM: 187300

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000477315Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification 20161018)
Likely benign
(Jun 14, 2016)
germlineclinical testing

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000603466ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)
Benign
(Oct 9, 2023)
germlineclinical testing

Citation Link,

SCV004805866ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen HHT ACMG Specifications ENG V1.1.0)
Likely Benign
(Mar 15, 2024)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000477315.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603466.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen, SCV004805866.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_001114753.3: c.1510G>A variant in ENG is a missense variant predicted to cause substitution of valine by methionine at amino acid 504 (p.Val504Met). The filtering allele frequency (the lower threshold of the 95% CI of 225/24916) of the c.1510G>A variant in ENG is 0.007757 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in trans with the variant c.23T>C, p.Leu8Pro (PMID: 19767588), which is classified as pathogenic by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, in affected family members with HHT. The phase of the variants was confirmed by parental testing (BP2). The computational predictor REVEL gives a score of 0.239, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP2, BS3_Supporting (specification version 1.0.0; 1/4/2024).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024