NM_001114753.3(ENG):c.694C>T (p.Arg232Trp) AND Hereditary hemorrhagic telangiectasia type 1

Clinical significance:Uncertain significance (Last evaluated: Mar 23, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001001189.2

Allele description [Variation Report for NM_001114753.3(ENG):c.694C>T (p.Arg232Trp)]

NM_001114753.3(ENG):c.694C>T (p.Arg232Trp)

Gene:
ENG:endoglin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q34.11
Genomic location:
Preferred name:
NM_001114753.3(ENG):c.694C>T (p.Arg232Trp)
HGVS:
  • NC_000009.12:g.127825353G>A
  • NG_009551.1:g.34416C>T
  • NM_000118.3:c.694C>T
  • NM_000118.3:c.694C>T
  • NM_001114753.3:c.694C>TMANE SELECT
  • NM_001278138.2:c.148C>T
  • NP_000109.1:p.Arg232Trp
  • NP_000109.1:p.Arg232Trp
  • NP_001108225.1:p.Arg232Trp
  • NP_001265067.1:p.Arg50Trp
  • LRG_589t1:c.694C>T
  • LRG_589t1:c.694C>T
  • LRG_589:g.34416C>T
  • LRG_589p1:p.Arg232Trp
  • LRG_589p1:p.Arg232Trp
  • NC_000009.11:g.130587632G>A
  • NC_000009.11:g.130587632G>A
Protein change:
R232W
Links:
dbSNP: rs200372420
NCBI 1000 Genomes Browser:
rs200372420
Molecular consequence:
  • NM_000118.3:c.694C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001114753.3:c.694C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278138.2:c.148C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary hemorrhagic telangiectasia 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
SCV001158345ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Mar 28, 2019)
germlineclinical testing

Citation Link,

SCV001548511Johns Hopkins Genomics, Johns Hopkins Universitycriteria provided, single submitter
Uncertain significance
(Mar 23, 2021)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Sequencing of TGF-beta pathway genes in familial cases of intracranial aneurysm.

Santiago-Sim T, Mathew-Joseph S, Pannu H, Milewicz DM, Seidman CE, Seidman JG, Kim DH.

Stroke. 2009 May;40(5):1604-11. doi: 10.1161/STROKEAHA.108.540245. Epub 2009 Mar 19.

PubMed [citation]
PMID:
19299629
PMCID:
PMC2678560

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001158345.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ENG c.694C>T; p.Arg232Trp variant (rs200372420) is reported in the literature in an individual affected with intracranial aneurysm but also in several healthy controls (Santiago-Sim 2009). This variant is found in the African population with an overall allele frequency of 0.06% (15/24588 alleles) in the Genome Aggregation Database. The arginine at codon 232 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Arg232Trp variant is uncertain at this time. References: Santiago-Sim T et al. Sequencing of TGF-beta pathway genes in familial cases of intracranial aneurysm. Stroke. 2009 May;40(5):1604-11.

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

From Johns Hopkins Genomics, Johns Hopkins University, SCV001548511.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

ENG c.694C>T has been previously reported in an individual with an intracranial aneurysm, but also in three apparently healthy individuals. This ENG variant (rs200372420) is rare (<0.1%) in a large population dataset (gnomAD: 22/279074 total alleles; 0.008%; no homozygotes) and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging. The arginine residue at this position is evolutionarily conserved across most of the mammals assessed, however a tryptophan is present at this position in two mammalian species. We consider the clinical significance of ENG c.694C>T to be uncertain at this time.

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

Last Updated: Oct 25, 2021

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