Submissions for variant NM_000218.3(KCNQ1):c.1513C>T (p.Gln505Ter)

dbSNP: rs397508091

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000614087	SCV000731657	likely pathogenic	Congenital long QT syndrome	2017-07-24	criteria provided, single submitter	clinical testing	The p.Gln505X variant in KCNQ1 has been reported in 1 individual with long QT sy ndrome (Kapa 2009, Kapplinger 2009), and was absent from large population studie s. This nonsense variant leads to a premature termination codon at position 505, which is predicted to lead to a truncated or absent protein. Heterozygous loss- of-function variants in KCNQ1 are known to cause autosomal dominant long QT synd rome 1 (also known as Romano-Ward syndrome). In the compound heterozygous or hom ozygous state, these variants are associated with autosomal recessive Jervell an d Lange-Nielsen syndrome (JLNS). In summary, although additional studies are req uired to fully establish its clinical significance, the p.Gln505X variant is lik ely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622334	SCV000740346	pathogenic	Long QT syndrome	2017-07-25	criteria provided, single submitter	clinical testing
GeneDx	RCV001659985	SCV001872965	pathogenic	not provided	2024-05-21	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has been reported in an individual with LQTS in the published literature (PMID: 19716085); This variant is associated with the following publications: (PMID: 25525159, 31447099, 19716085)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000622334	SCV002141573	pathogenic	Long QT syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln505*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 19841300). ClinVar contains an entry for this variant (Variation ID: 52984). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002390193	SCV002709804	pathogenic	Cardiovascular phenotype	2020-09-18	criteria provided, single submitter	clinical testing	The p.Q505* pathogenic mutation (also known as c.1513C>T), located in coding exon 11 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1513. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation has been detected in long QT syndrome (LQTS) cohorts, including at least one homozygous case with sensorineural hearing loss reported; however QTc values were not provided (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; (Kapa S et al. Circulation, 2009 Nov;120:1752-60; Millat G et al. Clin. Chim. Acta, 2011 Jan;412:203-7). In addition to the clinical data presented in the literature, 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577463	SCV000678865	not provided	Long QT syndrome 1		no assertion provided	literature only