ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1512dup (p.Arg505fs) (rs397508104)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046040 SCV000074053 pathogenic Long QT syndrome 2019-01-07 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the KCNQ1 gene (p.Arg632Glnfs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acids of the KCNQ1 protein. While this variant is present in population databases (rs777555803), the frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in several individuals affected with long QT syndrome, Jervell and Lange-Nielsen syndrome and recessive Romano–Ward syndrome (PMID: 10024302, 23098067, 23631430, 25187895, 19825999, 16981927). This variant is also known as 1893insC, insC1893–1894 (P631fs/19), 1893insC P631+19X and p.G629fs in the literature. ClinVar contains an entry for this variant (Variation ID: 53027). Experimental studies have shown that this frameshift change results in a trafficking defect and complete loss of electrophysiological function of the KvLQT1 channel (PMID: 19825999). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182288 SCV000234591 pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing The c.1893dupC variant in the KCNQ1 gene, also reported as insC1893-1894 due to the use of alternate nomenclature, has previously been reported in association with LQTS (Neyroud et al., 1999; Splawski et al., 2000; Novotny et al., 2006; Kapplinger et al., 2009; Stattin et al., 2012). Sung et al. (2014) identified this variant in a 14 month-old boy diagnosed with JLNS, who also harbored a large deletion in the KCNQ1 gene in trans. This individual's brother also harbored both KCNQ1 variants; he had a prolonged QT interval but normal hearing. Novotny et al. (2006) identified this variant in the homozygous state in a patient with an extremely prolong QT interval but normal hearing. Parents were confirmed to be heterozygous and were asymptomatic. In addition, the c.1893dupC variant has been observed in multiple unrelated individuals referred for LQTS testing at GeneDx.The c.1893dupC variant causes a shift in reading frame starting at codon arginine 632, changing it to a glutamine, and creating a premature stop codon at position 20 of the new reading frame, denoted p.Arg632GlnfsX20. This variant is expected to result in an abnormal, truncated protein product with the last 45 amino acid residues replaced by 19 incorrect amino acid residues. Sato et al. (2009) performed functional studies which demonstrated this variant results in a trafficking defect and complete loss of electrophysiological function of the KvLQT1 channel. Furthermore, the c.1893dupC variant is not observed in large population cohorts (Lek et al., 2016). In summary, c.1893dupC in the KCNQ1 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000622116 SCV000737795 likely pathogenic Cardiovascular phenotype 2017-12-19 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),Deficient protein function in appropriate functional assay(s)
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000003284 SCV000839973 pathogenic Long QT syndrome 1 2018-01-30 criteria provided, single submitter clinical testing This c.1893dup (p.Arg632Glnfs*20) variant in the KCNQ1 gene has been reported in 1/93 unrelated LQTS patients [PMID:10024302] while observed with extremely low allele frequency in general population according to gnomad database. This variant has also been reported in trans with an exon7-10 deletion of KCNQ1 in 2 LQTS brothers while both parents are normal carriers. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidences, c.1893dup (p.Arg632Glnfs*20) variant in the KCNQ1 gene is classified as pathogenic.
OMIM RCV000003284 SCV000023442 pathogenic Long QT syndrome 1 1999-02-19 no assertion criteria provided literature only

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