ClinVar Miner

Submissions for variant NM_000501.4(ELN):c.647G>T (p.Gly216Val) (rs145612009)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728083 SCV000855615 uncertain significance not provided 2017-07-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765972 SCV000897394 uncertain significance Cutis laxa, autosomal dominant 1; Williams syndrome; Supravalvar aortic stenosis 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000728083 SCV000250061 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing The G216V variant in the ELN gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The G216V variant was not observed with a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The G216V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (P211S, P220L) have been reported in association with cutis laxa and supravalvular aortic stenosis, respectively, supporting the functional importance of this region of the protein. We interpret G216V as a variant of unknown significance. This variant has been observed to be paternally inherited. This variant was found in ELN
Invitae RCV000531891 SCV000622214 uncertain significance Supravalvar aortic stenosis 2017-08-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 216 of the ELN protein (p.Gly216Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs145612009, ExAC 0.05%), 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 ELN-related disease. ClinVar contains an entry for this variant (Variation ID: 213192). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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