ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.322C>T (p.His108Tyr) (rs756897517)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000396856 SCV000477352 uncertain significance 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001373160 SCV001569864 uncertain significance Hereditary hemorrhagic telangiectasia 2020-09-02 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 108 of the ENG protein (p.His108Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs756897517, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with ENG-related conditions. ClinVar contains an entry for this variant (Variation ID: 365094). Experimental studies have shown that a different variant (c.321_322delinsTT) giving rise to the same protein effect does not substantially affect ENG protein function (PMID: 25312062). 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.

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