ClinVar Miner

Submissions for variant NM_003640.5(ELP1):c.1886G>A (p.Arg629His) (rs148378319)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724344 SCV000226616 uncertain significance not provided 2017-01-09 criteria provided, single submitter clinical testing
GeneDx RCV000214808 SCV000278985 uncertain significance not specified 2017-10-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the IKBKAP gene. The R629H variant hasbeen reported previously in an individual with paclitaxel-induced peripheral neuropathy; however, asecond IKBKAP variant was not reported, and additional information was not provided(Apellaniz-Ruiz et al., 2016). The R629H variant is observed in 50/10144 (0.5%) alleles fromindividuals of Ashkenazi Jewish background, in large population cohorts (Lek et al., 2016). TheR629H variant is a conservative amino acid substitution, which is not likely to impact secondaryprotein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis isinconsistent in its predictions as to whether or not the variant is damaging to the proteinstructure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000316773 SCV000476572 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.
Invitae RCV000724344 SCV000563263 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000316773 SCV000884032 uncertain significance Familial dysautonomia 2019-01-07 criteria provided, single submitter clinical testing The ELP1 c.1886G>A; p.Arg629His variant (rs148378319), is reported in the literature in a cohort of Paclitaxel-induced peripheral neuropathy, but has been found in association with familial dysautonomia with no second variant detected (Apellaniz-Ruiz 2017). This variant is reported as uncertain significance or likely benign in ClinVar (Variation ID: 194739), and is found in the general population with an overall allele frequency of 0.019% (550/282,634 alleles) in the Genome Aggregation Database. The arginine at codon 629 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg629His variant is uncertain at this time. References: Apellaniz-Ruiz et al. Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy. Clin Cancer Res. 2017 Mar 1;23(5):1227-1235.
Integrated Genetics/Laboratory Corporation of America RCV000214808 SCV000919538 uncertain significance not specified 2018-03-19 criteria provided, single submitter clinical testing Variant summary: IKBKAP c.1886G>A (p.Arg629His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 276958 control chromosomes. The observed variant frequency is slightly above the estimated maximal expected allele frequency for a pathogenic variant in IKBKAP causing Familial Dysautonomia phenotype (0.0018), suggesting that the variant may be benign. c.1886G>A has been reported in the literature in individuals affected with glioma and induced peripheral neuropathy, but not familial dysautonomia. Therefore, these reports do not provide unequivocal conclusions about an association of the variant with familial dysautonomia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with two classifying the variant as uncertain significance and one classifying at likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000724344 SCV001155707 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing
Natera, Inc. RCV000316773 SCV001462235 likely benign Familial dysautonomia 2020-04-14 no assertion criteria provided clinical testing

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