ClinVar Miner

Submissions for variant NM_000501.4(ELN):c.460G>A (p.Val154Met) (rs145669576)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522898 SCV000618179 uncertain significance not provided 2019-01-10 criteria provided, single submitter clinical testing The V154M variant has not been published as pathogenic or been reported as benign to our knowledge. This substitution occurs at a position that is conserved in mammals. Nevertheless, the V154M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, V154M was observed in 28/126,484 (0.02%) alleles from individuals of European (Non-Finnish) background in large population cohorts (Lek et al., 2016).
Illumina Clinical Services Laboratory,Illumina RCV001158464 SCV001320106 likely benign Supravalvar aortic stenosis 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.
Illumina Clinical Services Laboratory,Illumina RCV001158465 SCV001320107 benign Cutis laxa, autosomal dominant 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV001158464 SCV001411819 uncertain significance Supravalvar aortic stenosis 2019-01-22 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 154 of the ELN protein (p.Val154Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs145669576, ExAC 0.03%), 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: 449781). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; 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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