ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1762G>A (p.Val588Ile) (rs201768056)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233031 SCV000283532 uncertain significance Hereditary hemorrhagic telangiectasia 2020-09-11 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 588 of the ENG protein (p.Val588Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs20rs201768056, ExAC 0.07%) but has not been reported in the literature in individuals with a ENG-related disease. ClinVar contains an entry for this variant (Variation ID: 237024). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
GeneDx RCV000414391 SCV000491731 uncertain significance not specified 2016-11-15 criteria provided, single submitter clinical testing The V588I variant of uncertain significance in the ENG gene has not been published as a pathogenicor benign variant to our knowledge. However, it is classified in ClinVar as a variant of uncertainsignificance in association with HHT by another clinical laboratory (ClinVar SCV000283532.1;Landrum et al., 2016). This variant was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. The V588I variant is a conservative amino acidsubstitution, which is not likely to impact secondary protein structure as these residues share similarproperties. This substitution also occurs at a position that is not conserved. Consequently, themajority of in silico tools predict V588I likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV001169423 SCV001332119 likely benign Hereditary hemorrhagic telangiectasia type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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