ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1190T>G (p.Val397Gly) (rs199472790)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046000 SCV000074013 likely pathogenic Long QT syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 524 of the KCNQ1 protein (p.Val524Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with long QT syndrome (PMID: 14678125, 15840476, 17470695, 22949429). It has also been observed in several individuals with autosomal recessive long QT syndrome (PMID: 15466642, 23728945). ClinVar contains an entry for this variant (Variation ID: 52994). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000182201 SCV000234504 likely pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing The V524G likely pathogenic variant in the KCNQ1 gene has previously been reported in multiple individuals with LQTS or referred for LQTS genetic testing (Zareba et al., 2003; Choi et al., 2004; Moss et al., 2004; Tester et al., 2005; Kapa et al., 2009; Kapplinger et al., 2009; Giudicessi et al., 2012; Giudicessi et al., 2013). V524G was identified in two siblings who also harbored a frameshift variant in KCNQ1 (Giudicessi et al., 2013). Both presented with a more severe phenotype (QTc >550) compared to relatives who harbored only a single variant (Giudicessi et al., 2013). In addition, V524G was identified in an unrelated female with a QTc of 499 ms who also harbored a second missense variant in KCNQ1. Her brother harbored only the second variant and had a less severe phenotype (Giudicessi et al., 2013). This variant has also been observed in other unrelated individuals referred for LQTS genetic testing at GeneDx, and was observed to segregate with disease in multiple affected relatives from this patient's family. The V524G variant is not observed in large population cohorts (Lek et al., 2016). Although the V524G variant is a conservative amino acid substitution, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, V524G in the KCNQ1 gene is interpreted as a likely pathogenic variant.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057599 SCV000089118 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:14678125;PMID:15466642;PMID:15840476;PMID:19716085;PMID:19841300;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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