ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.107del (p.Leu36fs) (rs397508112)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182264 SCV000234567 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing The c.488delT pathogenic variant in the KCNQ1 gene has been reported in association with LQTS and sudden unexplained death (Choi et al., 2004; Tester et al., 2005; Kapplinger et al., 2009; Kapa et al., 2009; Tester et al., 2012), and has been observed in multiple individuals referred for LQTS genetic testing at GeneDx. This variant causes a shift in reading frame starting at codon leucine 163, changing it to an arginine, and creating a premature stop codon at position 74 of the new reading frame, denoted p.Leu163ArgfsX74. 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 the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.488delT variant has not been observed in large population cohorts (Lek et al., 2016).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000217623 SCV000271231 likely pathogenic Romano-Ward syndrome; Jervell and Lange-Nielsen syndrome; Rare genetic deafness 2015-02-02 criteria provided, single submitter clinical testing The p.Leu163fs variant in KCNQ1 has been previously reported in at least 1 indiv idual with long QT syndrome and is absent from large population databases (Choi 2004, Tester 2005, Kapplinger 2009). This variant is predicted to cause a frames hift, which alters the protein's amino acid sequence beginning at codon 163 and leads to a premature stop codon 74 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Loss of function variants in KCNQ1 lead to Jervell and Lange-Nielsen syndrome (JLNS) in compound heterozy gous and homozygous individuals, while dominant-negative and loss-of-function va riants in KCNQ1 have been shown to cause dominantly inherited long QT syndrome 1 (also known as Romano-Ward syndrome)in heterozygous individuals. In summary, al though additional studies are required to fully establish its clinical significa nce, this variant meets our criteria to be classified as likely pathogenic (http ://www.partners.org/personalizedmedicine/LMM) based upon its impact to the prote in.
Ambry Genetics RCV000618367 SCV000737922 pathogenic Cardiovascular phenotype 2016-08-04 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)
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709731 SCV000839969 pathogenic Long QT syndrome 1 2017-05-24 criteria provided, single submitter clinical testing The c.488del (p.Leu163Argfs*74) variant in the KCNE1 gene has been reported in a patient from a cohort of 388 patients referred for LQTS genetic testing with a family history of a first degree relative with a cardiac event during swimming [reported as V162fs in PMID 15840476, 15840476]. This variant has not been observed in the ExAC database but has been assessed in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/53050). This one bp deletion in exon 3 results in a frameshift and the creation of a premature stop codon, and is predicted to result in a loss of function of KCNQ1. This variant is thus classified as pathogenic

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