Submissions for variant NM_003640.5(ELP1):c.3213G>C (p.Glu1071Asp)

gnomAD frequency: 0.00058  dbSNP: rs140024352

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001201381	SCV000751659	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1071 of the ELP1 protein (p.Glu1071Asp). This variant is present in population databases (rs140024352, gnomAD 0.09%), 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 ELP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 526197). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Illumina Laboratory Services, Illumina	RCV000630694	SCV001328520	uncertain significance	Familial dysautonomia	2018-01-13	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.
Ambry Genetics	RCV002461938	SCV002756293	uncertain significance	Inborn genetic diseases	2021-12-08	criteria provided, single submitter	clinical testing	The p.E1071D variant (also known as c.3213G>C), located in coding exon 28 of the IKBKAP gene, results from a G to C substitution at nucleotide position 3213. The glutamic acid at codon 1071 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001201381	SCV003918721	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001201381	SCV004563084	uncertain significance	not provided	2023-11-02	criteria provided, single submitter	clinical testing	The ELP1 c.3213G>C; p.Glu1071Asp variant (rs140024352), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 526197). This variant is found in the general population with an overall allele frequency of 0.05% (133/282,676 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.025). Due to limited information, the clinical significance of this variant is uncertain at this time.