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

gnomAD frequency: 0.00006  dbSNP: rs201012726

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198008	SCV000250040	uncertain significance	not provided	2023-05-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11735026, 11175284, 15990952, 34426522, 29501665)
Illumina Laboratory Services, 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 Laboratory Services, 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000279620	SCV001439930	uncertain significance	Cutis laxa, autosomal dominant 1	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000334634	SCV002162299	uncertain significance	Supravalvar aortic stenosis	2023-12-07	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 220 of the ELN protein (p.Pro220Leu). This variant is present in population databases (rs201012726, gnomAD 0.01%). This missense change has been observed in individual(s) with supravalvular aortic stenosis (PMID: 11175284). ClinVar contains an entry for this variant (Variation ID: 213175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ELN protein function with a negative predictive value of 80%. 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.