ClinVar Miner

Submissions for variant NM_003640.5(ELP1):c.2948A>T (p.Gln983Leu) (rs749200669)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000229285 SCV000291959 uncertain significance not provided 2017-02-09 criteria provided, single submitter clinical testing The Q983L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q983L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000798294 SCV000937901 uncertain significance Familial dysautonomia 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces glutamine with leucine at codon 983 of the IKBKAP protein (p.Gln983Leu). The glutamine residue is weakly conserved and there is a moderate physicochemical difference between glutamine and leucine. This variant is present in population databases (rs749200669, ExAC 0.004%). This variant has not been reported in the literature in individuals with IKBKAP-related disease. ClinVar contains an entry for this variant (Variation ID: 242310). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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