ClinVar Miner

Submissions for variant NM_153033.4(KCTD7):c.335G>A (p.Arg112His) (rs774026720)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188023 SCV000241626 likely pathogenic not provided 2014-12-05 criteria provided, single submitter clinical testing The R112H variant that is likely pathogenic has been identified in the KCTD7 gene. The R112H variant has not been published as a mutation, nor has it been reported as a benign polymorphism 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. This substitution alters a highly conserved position predicted to be within the BTB domain of the KCTD7 protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R112H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000761541 SCV000891686 pathogenic Epilepsy, progressive myoclonic 3 2017-12-30 criteria provided, single submitter clinical testing
Invitae RCV000761541 SCV001493420 uncertain significance Epilepsy, progressive myoclonic 3 2020-02-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 112 of the KCTD7 protein (p.Arg112His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs774026720, ExAC 0.001%). This variant has been observed in individual(s) with clinical features of epilepsy and neurodevelopmental disorders (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 206015). 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 disruptive, 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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