ClinVar Miner

Submissions for variant NM_003640.5(ELP1):c.2803A>T (p.Thr935Ser) (rs145484092)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757403 SCV000885609 uncertain significance not provided 2017-06-15 criteria provided, single submitter clinical testing The p.Thr935Ser variant (rs14548409) has been reported as a variant of uncertain significance that was detected twice in a large cohort of patients with idiopathic peripheral neuropathy (Antoniardi 2015). This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 364564). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in European populations of 0.008% (identified on 10 out of 126,420 chromosomes). The threonine at codon 935 is moderately conserved (Alamut software v2.9.0), however several species including cape golden mole, lizard, Atlantic cod and lamprey have a serine at this position, suggesting this change may be evolutionary tolerated. Computational analyses return mixed predictions regarding the effect on IKBKAP protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing).
Illumina Clinical Services Laboratory,Illumina RCV000351107 SCV000476558 uncertain significance Familial dysautonomia 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000351107 SCV000816487 uncertain significance Familial dysautonomia 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 935 of the IKBKAP protein (p.Thr935Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs145484092, ExAC 0.003%). This variant has not been reported in the literature in individuals with IKBKAP-related disease. ClinVar contains an entry for this variant (Variation ID: 364564). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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