Submissions for variant NM_000501.4(ELN):c.1537G>A (p.Val513Ile)

gnomAD frequency: 0.00007  dbSNP: rs372788076

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478684	SCV000573476	uncertain significance	not provided	2017-02-20	criteria provided, single submitter	clinical testing	The V513I variant of uncertain significance in the ELN gene has not been published as pathogenic or benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, V513I is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution also occurs at a position not conserved across species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Lastly, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with ELN-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470874	SCV002767930	uncertain significance	Cutis laxa, autosomal dominant 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Dominant negative is suggested and loss of function is a known mechanism of disease in this gene and are associated with autosomal dominant cutis laxa (ADCL; MIM#123700), and supravalvar aortic stenosis (SVAS; MIM#185500), respectively (PMID: 29501665). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMIDs: 19844261, 10942104, 31577255). (I) 0115 - Variants in this gene are known to have variable expressivity. Carrier parents have been reported with a milder presentation (PMIDs: 10942104, 31577255). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v2: 22 heterozygotes, 0 homozygotes), with a bias in the European population. (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely benign (LOVD) and VUS (ClinVar) in a diagnostic setting, however no condition was provided. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV002525947	SCV003451704	uncertain significance	Supravalvar aortic stenosis	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 542 of the ELN protein (p.Val542Ile). This variant is present in population databases (rs372788076, gnomAD 0.01%). 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: 423742). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002526957	SCV003739274	likely benign	Inborn genetic diseases	2022-01-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.