Submissions for variant NM_003640.5(ELP1):c.2825G>A (p.Arg942Gln)

dbSNP: rs149845612

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000757401	SCV000291942	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in two individuals with CMT1 and hereditary motor neuropathy, respectively (Antoniadi et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26392352)
Invitae	RCV000757401	SCV000626017	uncertain significance	not provided	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 942 of the ELP1 protein (p.Arg942Gln). This variant is present in population databases (rs149845612, gnomAD 0.09%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease and/or hereditary motor neuropathy (PMID: 26392352). ClinVar contains an entry for this variant (Variation ID: 242293). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757401	SCV000885605	benign	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001166669	SCV001329067	uncertain significance	Familial dysautonomia	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291611	SCV002584773	uncertain significance	Medulloblastoma	2022-12-19	criteria provided, single submitter	clinical testing	The ELP1 c.2825G>A (p.Arg942Gln) missense change has a maximum subpopulation frequency of 0.089% in gnomAD v2.1.1 including one homozygote (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with Charcot-Marie-Tooth disease and in an individual with hereditary motor neuropathy (PMID: 26392352). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV004020902	SCV002755417	uncertain significance	not specified	2022-04-20	criteria provided, single submitter	clinical testing	The p.R942Q variant (also known as c.2825G>A), located in coding exon 25 of the IKBKAP gene, results from a G to A substitution at nucleotide position 2825. The arginine at codon 942 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly 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.
Natera, Inc.	RCV001166669	SCV001461192	benign	Familial dysautonomia	2020-05-30	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000757401	SCV001917844	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000757401	SCV001927233	uncertain significance	not provided		no assertion criteria provided	clinical testing