Submissions for variant NM_000501.4(ELN):c.1675G>A (p.Val559Ile)

gnomAD frequency: 0.00015  dbSNP: rs560081099

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627827	SCV000748707	uncertain significance	Supravalvar aortic stenosis	2023-11-21	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 588 of the ELN protein (p.Val588Ile). This variant is present in population databases (rs560081099, gnomAD 0.07%), 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: 524219). 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	RCV000762455	SCV000892777	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	ELN: BP4
Fulgent Genetics, Fulgent Genetics	RCV000765973	SCV000897395	uncertain significance	Cutis laxa, autosomal dominant 1; Williams syndrome; Supravalvar aortic stenosis	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002533162	SCV003552042	uncertain significance	Inborn genetic diseases	2022-07-14	criteria provided, single submitter	clinical testing	The c.1675G>A (p.V559I) alteration is located in exon 25 (coding exon 25) of the ELN gene. This alteration results from a G to A substitution at nucleotide position 1675, causing the valine (V) at amino acid position 559 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767452	SCV005381090	likely benign	not specified	2024-08-14	criteria provided, single submitter	clinical testing	Variant summary: ELN c.1762G>A (p.Val588Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251470 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 24-fold of the estimated maximal expected allele frequency for a pathogenic variant in ELN causing Supravalvar Aortic Stenosis phenotype (3.1e-05). To our knowledge, no occurrence of c.1762G>A in individuals affected with Supravalvar Aortic Stenosis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 524219). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004533301	SCV004737869	likely benign	ELN-related disorder	2022-01-31	no assertion criteria provided	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).