NM_000118.3(ENG):c.1586G>A (p.Arg529His) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Mar 23, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000755259.2

Allele description [Variation Report for NM_000118.3(ENG):c.1586G>A (p.Arg529His)]

NM_000118.3(ENG):c.1586G>A (p.Arg529His)

Genes:
ENG:endoglin [Gene - OMIM - HGNC]
LOC102723566:uncharacterized LOC102723566 [Gene]
Variant type:
single nucleotide variant
Cytogenetic location:
9q34.11
Genomic location:
Preferred name:
NM_000118.3(ENG):c.1586G>A (p.Arg529His)
Other names:
p.R529H:CGC>CAC
HGVS:
  • NC_000009.12:g.127818220C>T
  • NG_009551.1:g.41549G>A
  • NM_000118.3:c.1586G>A
  • NM_001114753.2:c.1586G>A
  • NM_001278138.1:c.1040G>A
  • NP_000109.1:p.Arg529His
  • NP_001108225.1:p.Arg529His
  • NP_001265067.1:p.Arg347His
  • LRG_589t1:c.1586G>A
  • LRG_589t2:c.1586G>A
  • LRG_589:g.41549G>A
  • LRG_589p1:p.Arg529His
  • LRG_589p2:p.Arg529His
  • NC_000009.11:g.130580499C>T
  • NM_000118.2:c.1586G>A
  • P17813:p.Arg529His
  • p.(Arg529His)
Protein change:
R347H
Links:
UniProtKB: P17813#VAR_070299; dbSNP: rs863223538
NCBI 1000 Genomes Browser:
rs863223538
Molecular consequence:
  • NM_000118.3:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001114753.2:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001278138.1:c.1040G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000250085GeneDxcriteria provided, single submitter
Uncertain significance
(Mar 23, 2018)
germlineclinical testing

Citation Link,

SCV000603461ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Mar 23, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000250085.13

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

Description

The R529H variant in the ENG gene has been reported multiple times in association with HHT (Bossler et al., 2006; Gedge et al., 2007; Bayrak-Toydemir et al., 2008; Richards-Yutz et al., 2010; Nishida et al., 2012). Bossler et al. (2006) originally reported R529H in a mother-daughter pair, as well as in an unrelated proband; both families had clinical characteristics of HHT. Bayrak-Toydemir et al. (2008) demonstrated that the R529H variant segregated with HHT phenotype in four affected relatives within the same family. The R529H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, R529H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Although this substitution occurs at a position that is conserved in mammals, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no definitively pathogenic missense variants in the same or nearby residues have been reported in the Human Gene Mutation Database in association with HHT (Stenson et al., 2014).

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000603461.2

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

Description

The ENG c.1586G>A; p.Arg529His variant (rs863223538) has been reported in the literature in individuals with symptoms of HHT (Bossler 2006, Gedge 2007, Nishida 2012). The variant is listed in the ClinVar database (Variation ID: 213212). The variant is reported at a low allele frequency (1 out of 246166 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 529 is well conserved across species and computational algorithms predict this variant to be damaging to the protein (SIFT, PolyPhen2). Given the above information, this variant is classified as pathogenic. References: Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 27(7):667-75. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn.2007 9(2):258-65. Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 158A(11):2829-34.

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

Last Updated: May 10, 2021

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