ClinVar Miner

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

dbSNP: rs137853022
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Total submissions: 9
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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.
Invitae 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

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