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

gnomAD frequency: 0.00034  dbSNP: rs145612009

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000728083	SCV000250061	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Reported in two German individuals with a dilated aortic root and a biscuspid aortic valve (Girdauskas et al., 2017); however, it is unclear which reference transcript was used in this study and whether this represents the same variant identified here due to discrepant c. nomenclature provided (c.515G>T); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25256751, 19029017, 28387797)
Invitae	RCV000531891	SCV000622214	uncertain significance	Supravalvar aortic stenosis	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 216 of the ELN protein (p.Gly216Val). This variant is present in population databases (rs145612009, gnomAD 0.06%), 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: 213192). 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.
Eurofins Ntd Llc (ga)	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
Illumina Laboratory Services, Illumina	RCV001161674	SCV001323567	benign	Cutis laxa, autosomal dominant 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000531891	SCV001325207	likely benign	Supravalvar aortic stenosis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Revvity Omics, Revvity	RCV000728083	SCV003831890	uncertain significance	not provided	2020-09-05	criteria provided, single submitter	clinical testing