ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.1291G>A (p.Gly431Arg)

gnomAD frequency: 0.00001  dbSNP: rs746853951
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology RCV002254386 SCV002525528 uncertain significance Seizures, benign familial neonatal, 1; Developmental and epileptic encephalopathy, 7 2022-03-25 criteria provided, single submitter clinical testing The c.1291G>A variant is not present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS) and Indian Exome Database. The heterozygous state of the variant is present in Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD), at a very low frequency. The variant is not present in our in-house exome database. The variant was not previously reported to Clinvar, Human Genome Mutation Database (HGMD) and/or OMIM databases, in any affected individuals. Predictions from different in-silico pathogenicity prediction programs like SIFT, Polyphem-2, MutationTaster2, CADD, Varsome etc. are contradictory. Different algorithms to predict mRNA splicing abnormalities, predicted this variant to potentially affect splicing by activating a cryptic acceptor site, however these predictions were not confirmed by any publiahed transcriptional studies.
Labcorp Genetics (formerly Invitae), Labcorp RCV003588787 SCV004304046 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2023-10-07 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 431 of the KCNQ2 protein (p.Gly431Arg). This variant is present in population databases (rs746853951, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1691288). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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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