Submissions for variant NM_000501.4(ELN):c.1999C>T (p.Pro667Ser)

gnomAD frequency: 0.00031  dbSNP: rs142316834

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001579602	SCV000250031	likely benign	not provided	2020-09-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26343384)
Illumina Laboratory Services, Illumina	RCV000351619	SCV000469940	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.
Illumina Laboratory Services, Illumina	RCV000405378	SCV000469941	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.
Invitae	RCV000405378	SCV001415151	uncertain significance	Supravalvar aortic stenosis	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 729 of the ELN protein (p.Pro729Ser). This variant is present in population databases (rs142316834, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ELN-related conditions. ClinVar contains an entry for this variant (Variation ID: 213166). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001579602	SCV002563955	benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	ELN: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003927823	SCV004752412	likely benign	ELN-related condition	2021-06-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579602	SCV001807865	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001579602	SCV001928745	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001579602	SCV001969048	likely benign	not provided		no assertion criteria provided	clinical testing