ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.1316A>C (p.Lys439Thr) (rs368533266)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000315391 SCV000477327 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 RCV001201388 SCV000546114 uncertain significance Hereditary hemorrhagic telangiectasia 2019-09-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 439 of the ENG protein (p.Lys439Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs368533266, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with hereditary hemorrhagic telangiectasia who also had a likely pathogenic variant in ENG (PMID: 25312062). ClinVar contains an entry for this variant (Variation ID: 365088). This variant has been reported to 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757218 SCV000885364 uncertain significance not provided 2017-09-14 criteria provided, single submitter clinical testing The c.1316A>C; p.Lys439Thr variant (rs368533266) was reported in a patient that carried a deletion in exon 6 of the ENG gene (Mallet, 2015). Functional studies by Mallet (2015) also showed that the p.Lys439Thr is properly targeted to the cell surface and stimulates ALK1 signaling in response to BMP9, features that are otherwise reduced in defective ENG polypeptides. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.15 percent in the Ashkenazi Jewish population (identified on 15 out of 9,850 chromosomes), and is reported to the ClinVar database (Variation ID: 365088). The lysine at position 439 is moderately conserved considering 12 species (Alamut v2.9.0) and computational analyses of the p.Lys439Thr variant on protein structure and function indicate a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on these observations, the p.Lys439Thr variant is likely to be benign.

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