Submissions for variant NM_000501.4(ELN):c.1606G>T (p.Ala536Ser)

gnomAD frequency: 0.00001  dbSNP: rs374253638

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825921	SCV000967406	uncertain significance	not specified	2018-07-03	criteria provided, single submitter	clinical testing	The p.Ala536Ser variant in ELN has not been previously reported in individuals w ith pulmonary disease but has been identified in 1/5484 chromosomes of various p opulations by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs374253638). Computational prediction tools and conservation ana lysis suggest that the p.Ala536Ser variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala536Ser variant is uncertain. ACMG/AMP Criteria applied: PP3.
Illumina Laboratory Services, Illumina	RCV001161895	SCV001323807	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	RCV001161896	SCV001323808	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001161896	SCV002224679	uncertain significance	Supravalvar aortic stenosis	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 565 of the ELN protein (p.Ala565Ser). This variant is present in population databases (rs374253638, gnomAD 0.003%). This missense change has been observed in individual(s) with Takayasu’s arteritis (PMID: 26483232). ClinVar contains an entry for this variant (Variation ID: 667232). 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.
GeneDx	RCV002462192	SCV002757193	uncertain significance	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Has been reported using alternate nomenclature (c.1693 G>T; R565S) in an individual with supravalvular aortic stenosis who carried the clinical diagnosis of Takayasu's arteritis (Warejko et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29483232, 26483232)
Breakthrough Genomics, Breakthrough Genomics	RCV002462192	SCV005188533	uncertain significance	not provided		criteria provided, single submitter	not provided