ClinVar Miner

Submissions for variant NM_000501.4(ELN):c.659C>T (p.Pro220Leu) (rs201012726)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198008 SCV000250040 likely pathogenic not provided 2015-05-05 criteria provided, single submitter clinical testing The P220L variant in the ELN gene has been previously published as a mutation in a patient and his mother, both affected with supravalvular aortic stenosis (Metcalfe et al., 2000). The P220L variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P220L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. A missense mutation in a nearby residue (P211S) has been reported in association with cutis laxa, supporting the functional importance of this region of the protein. The P220L variant is a strong candidate for a disease-causing mutation, however the possibility it may be a rare benign variant cannot be excluded. This variant was found in ELN.
Illumina Clinical Services Laboratory,Illumina RCV000279620 SCV000469876 likely 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 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 RCV000334634 SCV000469877 uncertain significance 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, 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.

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