ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.184G>A (p.Gly62Arg) (rs104894252)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223880 SCV000516040 pathogenic not provided 2018-02-07 criteria provided, single submitter clinical testing The G189R pathogenic variant in the KCNQ1 gene has been reported previously in association with LQTS (Wang et al., 1996; Jongbloed et al., 1999; Nannenberg et al., 2012). The G189R variant was initially reported to segregate with disease in three members of a family who had LQTS (Wang et al., 1996). Subsequently, Jongbloed et al. (1999) reported that G189R segregated with a LQTS phenotype in two other unrelated families. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016). The G189R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, and functional studies show that the G189R variant results in loss of KCNQ1 channel function (Wang et al., 1999; Barsheshet et al., 2012). Furthermore, a variant in the same residue (G189E) and variants in nearby residues (L187P, R190W, R190L, R190Q) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue and this region of the protein.
OMIM RCV000003261 SCV000023419 pathogenic Long QT syndrome 1 1999-01-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057702 SCV000089221 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:8528244;PMID:10220144;PMID:17470695;PMID:10220144). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223880 SCV000280157 pathogenic not provided 2014-01-27 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Gly189Arg Based on the information reviewed below, we classify it as very likely disease causing. This variant has previously been reported in at least 3 unrelated individuals with LQTS. There is very strong published segregation data. Jongbloed et al. (1999) identified this variant in 2 Dutch families with LQT1. It segregated with disease in 17 affected members of one family (2 of them asymptomatic), and 3 affected members of the other (one of them asymptomatic). Wang et al. (1996) had previously reported that it segregated with disease in 3 affected siblings in a family with LQTS. Nannenberg et al. (2012) reported it in a Dutch family with LQT1 in which they traced the disease back centuries, although it is not clear if this family was included in Jongbloed et al. (According to OMIM, this variant used to be known as GLY60ARG, by Wang et al., and GLY94ARG.) Another variant at this same codon, Gly189Glu, has been reported in association with LQTS (HGMD cites Moss et al. 2007, Giudicessi et al. 2012, and another). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar glycine with a positively-charged arginine with a much bulkier side-chain. Glycine at this location is highly conserved across vertebrate species (it is an alanine in a species of falcon). Variation at nearby residues has been associated with LQTS, which may support the functional importance of this region of the protein: G179S, K183R, K183M, Y184H, Y184S, G186R, G186S, L187P, R190W, R190L, R190Q, L191P, R192C, R192H, R192P, F193L, A194P, R195W, I198V, S199A (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0. In vitro functional studies show that it results in a loss of KCNQ1 channel function (Wang et al. 1999, Barsheshet et al 2012). This residue is in the cytoplasmic S2-S3 linker. It is not entirely possible to tell from the location within the KCNQ1 protein if a variant causes disease. However, when Kapa et al. (2009) compared 388 “clinically definite” LQTS probands to ~1300 healthy controls, they found that LQTS cases were much more likely to have missense variants in the C-terminal cytoplasmic region of the KCNQ1 protein (amino acid residues 349-676), the pore region, transmembrane region, or linker region (residues 122-348)—rather than in the N-terminal domain (residues 1-121). Variants in the transmembrane-linker-pore domain of the protein were 24x more frequent in LQTS cases than in controls. In total the variant has not been seen in over 60,000 published controls and individuals from publicly available population datasets. The variant was not observed in published controls: 55 individuals (Jongbloed et al. 1999; didn’t check the other references). As of 6/5/2015, there is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. Our patient’s ancestry is Caucasian. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. This variant was not found in 1000 Genomes (http://browser.1000genomes.org/index.htm). The variant is not present in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases.

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