ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.186dup (p.Arg63fs) (rs397508117)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046086 SCV000074099 pathogenic Long QT syndrome 2018-01-18 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. This variant is not present in population databases (ExAC no frequency). This truncation has been reported to segregate with long QT syndrome in a large multigenerational family (PMID: 9164812) and to be present in the homozygous and compound heterozygous state in two patients affected with Jervell and Lange-Nielsen Syndrome (PMID: 9164812, 21118729). This variant is also known as 282–283insG in the literature. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182266 SCV000234569 pathogenic not provided 2018-06-28 criteria provided, single submitter clinical testing The c.567dupG pathogenic variant in the KCNQ1 gene has been previously reported in two individuals diagnosed with Jervell and Lange-Nielsen syndrome 1 (JLNS1) (Splawski et al., 1997; Rice et al., 2011). Splawski et al. (1997) first identified this variant, denoted as 282-283insG due to alternate nomenclature, in an homozygous infant with JLNS1 who had a family history of LQTS, syncope, and sudden cardiac death. Rice et al. (2011) subsequently reported c.567dupG in a compound heterozygous individual with JLNS1 who also harbored the R518X pathogenic variant in the KCNQ1 gene, and had a sibling with JLNS1 who died at a young age. The c.567dupG pathogenic variant was shown to segregate with LQTS in numerous heterozygous relatives in one family (Splawski et al., 1997), and at least one heterozygous relative in the other family (Rice et al., 2011). This variant causes a shift in reading frame starting at codon arginine 190, changing it to an alanine, and creating a premature stop codon at position 95 of the new reading frame, denoted p.Arg190AlafsX95. This 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. Multiple other frameshift variants in the KCNQ1 gene have been reported in Human Gene Mutation Database in association with LQTS and JLNS1 (Stenson et al., 2014). Furthermore, the c.567dupG variant has not been observed in large population cohorts (Lek et al., 2016). In summary, c.567dupG in the KCNQ1 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000617403 SCV000737518 pathogenic Cardiovascular phenotype 2016-05-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
OMIM RCV000003273 SCV000023431 pathogenic Jervell and Lange-Nielsen syndrome 1 1997-05-29 no assertion criteria provided literature only

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