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

gnomAD frequency: 0.00203  dbSNP: rs148378319

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724344	SCV000226616	uncertain significance	not provided	2017-01-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000724344	SCV000278985	likely benign	not provided	2021-05-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27582484)
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724344	SCV000563263	likely benign	not provided	2025-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000316773	SCV000884032	uncertain significance	Familial dysautonomia	2021-10-21	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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 Center for Human Genetics Tuebingen	RCV000724344	SCV001155707	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	ELP1: BP4, BS2
Ambry Genetics	RCV000214808	SCV002756037	likely benign	not specified	2019-09-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Natera, Inc.	RCV000316773	SCV001462235	likely benign	Familial dysautonomia	2020-04-14	no assertion criteria provided	clinical testing