ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.567dup (p.Arg190fs)

dbSNP: rs397508117
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046086 SCV000074099 pathogenic Long QT syndrome 2024-01-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg190Alafs*95) 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 Jervell and Lange-Nielsen Syndrome (PMID: 9164812, 21118729). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53069). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182266 SCV000234569 pathogenic not provided 2023-01-19 criteria provided, single submitter clinical testing Frameshift 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); This variant is associated with the following publications: (PMID: 9164812, 21118729, 19862833, 28595573, 27535533)
Ambry Genetics RCV000617403 SCV000737518 pathogenic Cardiovascular phenotype 2016-05-27 criteria provided, single submitter clinical testing The c.567dupG pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a duplication of G at nucleotide position 567, causing a translational frameshift with a predicted alternate stop codon (p.R190Afs*95). This alteration has previously been detected in multiple individuals with long QT syndrome and segregated with disease in one family, and was also identified in individuals with Jervell and Lange-Nielsen syndrome in the homozygous or compound heterozygous state with another KCNQ1 truncating mutation (Rice KS et al., Heart Rhythm 2011 Apr; 8(4):551-4; Splawski I et al., N. Engl. J. Med. 1997 May; 336(22):1562-7). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes RCV003319311 SCV004024172 pathogenic Long QT syndrome 1 2023-08-01 criteria provided, single submitter clinical testing
OMIM RCV000003273 SCV000023431 pathogenic Jervell and Lange-Nielsen syndrome 1 1997-05-29 no assertion criteria provided literature only

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