Submissions for variant NM_000218.3(KCNQ1):c.1343del (p.Pro448fs)

dbSNP: rs397508087

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001841630	SCV000234584	pathogenic	Cardiac arrhythmia	2013-09-25	criteria provided, single submitter	clinical testing	The c.1343delC mutation in the KCNQ1 gene has been reported in association with LQTS (Neyroud N et al., 1999). Neyroud et al. identified c.1343delC in two affected individuals with LQTS from one family. This mutation causes a shift in reading frame starting at codon Proline 448, changing it to a Glutamine, and creating a premature stop codon at position 18 of the new reading frame, denoted p.Pro448GlnfsX18. This mutation 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 mutations in the KCNQ1 gene have been reported in association with LQTS. Finally, the c.1343delC mutation 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. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380029	SCV001577956	pathogenic	Long QT syndrome	2023-05-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52977). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 10024302). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Pro448Glnfs*18) 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).
Ambry Genetics	RCV002381341	SCV002688776	pathogenic	Cardiovascular phenotype	2021-12-16	criteria provided, single submitter	clinical testing	The c.1343delC pathogenic mutation, located in coding exon 10 of the KCNQ1 gene, results from a deletion of one nucleotide at nucleotide position 1343, causing a translational frameshift with a predicted alternate stop codon (p.P448Qfs*18). This mutation has been reported in association with long QT syndrome (Neyroud N et al. Circ Res, 1999 Feb;84:290-7; Walsh R et al. Genet Med, 2021 01;23:47-58). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV003319306	SCV004024167	pathogenic	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing