Submissions for variant NM_000501.4(ELN):c.1339G>A (p.Ala447Thr)

gnomAD frequency: 0.00013  dbSNP: rs139335797

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000392949	SCV000469918	uncertain significance	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, 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.
Illumina Laboratory Services, Illumina	RCV000303284	SCV000469919	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.
GeneDx	RCV001355478	SCV001824355	uncertain significance	not provided	2020-11-12	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000303284	SCV002169675	uncertain significance	Supravalvar aortic stenosis	2024-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 447 of the ELN protein (p.Ala447Thr). This variant is present in population databases (rs139335797, 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: 360654). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
PreventionGenetics, part of Exact Sciences	RCV004530461	SCV004114672	uncertain significance	ELN-related disorder	2023-08-09	criteria provided, single submitter	clinical testing	The ELN c.1339G>A variant is predicted to result in the amino acid substitution p.Ala447Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-73471025-G-A), which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GeneDx	RCV000413993	SCV000492363	uncertain significance	not specified	2016-12-12	flagged submission	clinical testing	A variant of uncertain significance has been identified in the ELN gene. The A447T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A447T variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, this substitution occurs at a position that is conserved in mammals and A447T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355478	SCV001550377	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ELN p.Ala385Thr variant was not identified in the literature but was identified in dbSNP (ID: rs139335797), Clinvitae, LOVD 3.0, ClinVar (reported as a VUS for Cutis laxa, autosomal dominant and Supravalvar aortic stenosis by Illumina and reported as a VUS by GeneDx) and Cosmic (predicted pathogenic by FATHMM). The variant was identified in control databases in 18 of 281968 chromosomes at a frequency of 0.000064 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 4 of 30612 chromosomes (freq: 0.000131), European (non-Finnish) in 12 of 128864 chromosomes (freq: 0.000093) and African in 2 of 24798 chromosomes (freq: 0.000081); it was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The p.Ala385 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.