ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.2146G>C (p.Asp716His) (rs149324120)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187992 SCV000241595 uncertain significance not provided 2018-04-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNQ3 gene. The D716H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D716H variant is observed in 6/33582 (0.02%) alleles from individuals of Latino background (Lek et al., 2016). The D716H 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, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter 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 RCV000797329 SCV000936881 uncertain significance Benign familial neonatal seizures 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 716 of the KCNQ3 protein (p.Asp716His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs149324120, ExAC 0.03%). This variant has not been reported in the literature in individuals with KCNQ3-related disease. ClinVar contains an entry for this variant (Variation ID: 205986). 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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