ClinVar Miner

Submissions for variant NM_001114753.3(ENG):c.1019C>T (p.Pro340Leu)

gnomAD frequency: 0.00004  dbSNP: rs772135786
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756076 SCV000883792 likely benign not provided 2017-07-09 criteria provided, single submitter clinical testing The ENG c.1019C>T; p.Pro340Leu variant (rs772135786) is reported in the general population databases with an overall allele frequency of 0.003 percent (9/277054 alleles, Genome Aggregation Database). The proline at codon 340 is well conserved, but computational algorithms do not agree as to the affect this variant may have on the protein (SIFT: Damaging, PolyPhen2: Possibly Damaging, MutationTaster: Polymorphism). Our laboratory has identified this variant in individuals who also carry a pathogenic ENG variant. Based on the above information, this variant is considered likely benign.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001262049 SCV001439427 likely benign Telangiectasia, hereditary hemorrhagic, type 1 2018-01-01 criteria provided, single submitter research BS1 +BP2
Labcorp Genetics (formerly Invitae), Labcorp RCV002533781 SCV002952672 uncertain significance Hereditary hemorrhagic telangiectasia 2022-09-24 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 340 of the ENG protein (p.Pro340Leu). This variant is present in population databases (rs772135786, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia, however in one of these individuals a pathogenic variant was also identified in the ACVRL1 gene (PMID: 21158752). ClinVar contains an entry for this variant (Variation ID: 618084). 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 leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect ENG function (PMID: 25312062). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
PreventionGenetics, part of Exact Sciences RCV003983196 SCV004800037 likely benign ENG-related disorder 2023-05-05 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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