ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.694C>T (p.Arg232Trp) (rs200372420)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000808290 SCV000948392 uncertain significance Hereditary hemorrhagic telangiectasia 2020-08-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 232 of the ENG protein (p.Arg232Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs200372420, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with intracranial aneurysm (PMID: 19299629). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0. The tryptophan amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001189 SCV001158345 uncertain significance Hereditary hemorrhagic telangiectasia type 1 2019-03-28 criteria provided, single submitter clinical testing 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.
Johns Hopkins Genomics, Johns Hopkins University RCV001001189 SCV001548511 uncertain significance Hereditary hemorrhagic telangiectasia type 1 2021-03-23 criteria provided, single submitter clinical testing 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.

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