ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.1A>G (p.Met1Val) (rs118192185)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000421973 SCV000892665 likely pathogenic not provided 2018-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000421973 SCV000513366 likely pathogenic not provided 2017-09-28 criteria provided, single submitter clinical testing A c.1 A>G variant that is likely pathogenic has been identified in the KCNQ2 gene. The c.1 A>G variant has been reported previously in association with benign familial neonatal seizures and with early-onset epileptic encephalopathy; however parental studies and RNA/functional studies were not reported (Richards et al., 2004; Milh et al., 2015). The c.1 A>G variant is not observed in large population cohorts (Lek et al., 2016). This variant alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternative Methionine initiator codon. In the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded."
GeneReviews RCV000678067 SCV000041626 pathogenic Benign familial neonatal seizures 1 2016-03-31 no assertion criteria provided literature only BFNE (benign familial neonatal epilepsy)
Invitae RCV000552408 SCV000634056 pathogenic Early infantile epileptic encephalopathy 2018-03-28 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the KCNQ2 mRNA. The next in-frame methionine is located in exon 4 (p.Met174) and could potentially rescue the loss of initiator codon. While this variant is not present in population databases (rs118192185), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to segregate with disease in a family affected with benign familial neonatal seizures (PMID: 14985406, 25982755). ClinVar contains an entry for this variant (Variation ID: 21774). Experimental studies have not been reported for this initiation codon variant and it is currently unknown if translation is rescued by either an in-frame or out-of-frame methionine. However, a missense variant located upstream of the next in-frame methionine (p.Arg144Gln) has been determined to be pathogenic (PMID: 23934111, 25740509). This suggests that even if translation is rescued by an in-frame methionine, deletion of the N-terminal region of the KCNQ2 protein is likely to be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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