Submissions for variant NM_000218.3(KCNQ1):c.692_693dup (p.Phe232fs)

dbSNP: rs1589957697

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008398	SCV001168167	likely pathogenic	not provided	2018-10-18	criteria provided, single submitter	clinical testing	Although the c.692_693dupGC likely pathogenic variant in the KCNQ1 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon phenylalanine 232, changing it to an alanine, and creating a premature stop codon at position 6 of the new reading frame, denoted p.Phe232AlafsX6. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the KCNQ1 gene have been reported in Human Gene Mutation Database in association with KCNQ1-related disorders (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.692_693dupGC variant has not been observed in large population cohorts (Lek et al., 2016). In summary, c.692_693dupGC in the KCNQ1 gene is interpreted as a likely pathogenic variant.
Invitae	RCV002549288	SCV003222635	pathogenic	Long QT syndrome	2022-07-22	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817280). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. This sequence change creates a premature translational stop signal (p.Phe232Alafs*6) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833).