Submissions for variant NM_003640.5(ELP1):c.2087G>C (p.Arg696Pro)

dbSNP: rs137853022

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV000006459	SCV001193857	likely pathogenic	Familial dysautonomia	2019-12-09	criteria provided, single submitter	clinical testing	NM_003640.3(IKBKAP):c.2087G>C(R696P) is classified as likely pathogenic in the context of familial dysautonomia. Sources cited for classification include the following: PMID 11179008 and 11179021. Classification of NM_003640.3(IKBKAP):c.2087G>C(R696P) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380395	SCV001578458	pathogenic	not provided	2021-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 696 of the ELP1 protein (p.Arg696Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial dysautonomia (PMID: 11179008, 11179021, 12116234). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 11179008, 11179021, 12116234). ClinVar contains an entry for this variant (Variation ID: 6086). 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"). Experimental studies have shown that this missense change affects ELP1 function (PMID: 11179021). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006459	SCV002051086	pathogenic	Familial dysautonomia	2021-12-13	criteria provided, single submitter	clinical testing	Variant summary: IKBKAP c.2087G>C (p.Arg696Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 259280 control chromosomes (gnomAD and publication data). c.2087G>C has been reported in the literature in multiple individuals affected with Familial Dysautonomia (Slaugenhaupt_2001, Anderson_2001, Gutirrez_2017). These data indicate that the variant is very likely to be associated with disease. At least one function study reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Anderson_2001). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002482833	SCV002776476	pathogenic	Medulloblastoma; Familial dysautonomia	2021-11-11	criteria provided, single submitter	clinical testing
OMIM	RCV000006459	SCV000026642	pathogenic	Familial dysautonomia	2002-07-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000006459	SCV000734629	pathogenic	Familial dysautonomia		no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium	RCV000789660	SCV000929032	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV001380395	SCV001925728	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000006459	SCV002014564	not provided	Familial dysautonomia		no assertion provided	literature only	A rare variant identified in Ashkenazi Jews