ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.121G>A (p.Gly41Arg) (rs179489)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046066 SCV000074079 pathogenic Long QT syndrome 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 168 of the KCNQ1 protein (p.Gly168Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature to segregate with long QT syndrome (PMID: 9693036). It has also been reported in multiple individuals affected with long QT syndrome (PMID: 19841300, 23130128, 17905336, 10973849). ClinVar contains an entry for this variant (Variation ID: 53052). This variant identified in the KCNQ1 gene is located in the transmembrane S2 region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNQ1-topology. One experimental study has shown that this missense change causes a moderate decrease in channel current (PMID: 19490272). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000223900 SCV000234379 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing The G168R pathogenic variant has been reported in >20 individuals with LQTS in multiple publications (Splawski et al., 2000; Jongbloed et al., 2002; Beery et al., 2003; Kapplinger et al., 2009; Summers et al., 2010). Beery et al. (2003) reported a large family in which G168R segregated with an LQTS phenotype in six relatives. Summers et al. (2010) also reported a large Australian family with LQTS in which the G168R variant was identified in 12 affected individuals and one unaffected infant, but the variant was absent in four affected family members; the authors believe a second, unknown, disease-causing variant was segregating in this family. In addition, G168R was reported in the homozygous state in two Mexican siblings and an unrelated Indian individual with JLNS (Marquez et al., 2006; Vyas et al., 2016). The same amino acid substitution resulting from a different nucleotide change (c.502 G>C) has also been reported as a pathogenic variant in association with LQTS (Donger et al., 1997), and functional studies demonstrate G168R (nucleotide change not specified) results in a complete loss of channel function (Westenskow et al., 2004). Finally, the G168R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, G168R in the KCNQ1 gene is interpreted as a pathogenic variant.
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000234807 SCV000240226 pathogenic Long QT syndrome 1 2013-01-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000588586 SCV000695988 pathogenic Cardiovascular phenotype 2016-12-19 criteria provided, single submitter clinical testing Variant summary: The KCNQ1 c.502G>A (p.Gly168Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 122776 control chromosomes, but has been reported in numerous affected individuals in the literature, including multi-generational families in which the variant segregated with disease. Functional data has shown the variant alters potassium channel function (Barsheshet_2012, Jons_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000588586 SCV000736265 pathogenic Cardiovascular phenotype 2018-07-26 criteria provided, single submitter clinical testing Good segregation with disease (lod 1.5-3 = 5-9 meioses);Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV001179842 SCV001344630 pathogenic Arrhythmia 2019-05-30 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057684 SCV000089203 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:20186784;PMID:9693036;PMID:12402336;PMID:10973849;PMID:19716085;PMID:15051636;PMID:17905336;PMID:15840476;PMID:14678125;PMID:12566525;PMID:19841300;PMID:9386136). 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 RCV000223900 SCV000280154 pathogenic not provided 2013-11-13 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.Gly168Arg The Gly168Arg mutation in KCNQ1 has been reported multiple times in association with autosomal dominant long QT syndrome, and in vitro analysis has shown it to cause complete loss of potassium channel function. Strong segregation data comes from Beery et al. (2003). Gly168Arg segregated with disease in all 7 affected members of an LQTS family (from 4 generations). Gly168Arg is a chemically nonconservative amino acid change. It substitutes the smallest, nonpolar amino acid Glycine, which lacks a carbon side chain, with the bulkier positively-charged amino acid side chain of Arginine. The Glycine at position 168 is highly conserved across species. In silico analysis predicts the variant to be “probably damaging” (PolyPhen) and “deleterious” (SIFT). This variant has been reported in over 32 unrelated individuals with LQTS. It is not present in 1800 reported controls, nor in ~6450 individuals in the NHLBI ESP project. Donger et al. (1997) found this mutation in 5 individuals in one French family affected by LQT1. Four of these family members, as a group, had a mean QTc of 477+24 msec, while the fifth died suddenly before age 40. The Gly168Arg mutation was absent in 200 control alleles. Splawski et al. (2000) reported this variant in 7 out of 262 unrelated European and American probands with LQTS; it was absent from more than 400 control alleles. Jongbloed et al. (2002) identified 1 Gly168Arg variant among 32 Dutch and Belgian index patients; they report that a variant was classified as pathogenic if it “segregated with the disease in the family” and was absent from 100 control chromosomes. Van Langen et al. (2003) found Gly168Arg in 1 out of 40 consecutive, unrelated LQTS patients from the Netherlands and Belgium; it was absent from 100 control alleles. Westenskow et al. (2004) reported a family affected by 2 LQTS variants, of which Gly168Arg was one. The family member carrying Gly168Arg alone had a QTc in the normal range (440) and no history of syncope, while two family members who carried both variants had prolonged QTc (480 and 510) and syncope. Therefore, this particular study does not add convincing clinical evidence of pathogenicity. However, it does include in-vitro biophysical data, showing that Gly168Arg causes complete loss of channel function. Tester et al. (2005) reported the variant in 2 of 541 consecutive, unrelated patients referred to Mayo Clinic’s Sudden Death Genomics Laboratory for LQTS genetic testing. Moss et al. (2007) did an outcome study of 600 KCNQ1-variant-carrying patients (from 101 families) included in the US portion of the International LQTS Registry (n=425), the Netherlands’ LQTS Registry (n=93), and the Japanese LQTS Registry (n=82), and 44 of these 600 patients had the Gly168Arg variant. This made Gly168Arg the second-most common variant represented in the study. Chung et al. (2007) found it in 1 of 84 consecutive LQTS index cases tested in New Zealand (but not in 100 control chromosomes); she had a QTc of 500 msec, a history of syncope, and a first-degree relative who had died suddenly. Kapplinger et al. (2009) reported the Gly168Arg variant in 15 out of 2500 unrelated individuals diagnosed with LQTS and consecutively referred for genetic testing through PGxHealth; they did not find the variant in more than 2,600 reference alleles from individuals of diverse ethnicity (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). The variant has also been reported by Marquez et al. (2006) in a homozygous state in two affected siblings, from a Mexican family, diagnosed with Jervell and Lange-Nielsen Syndrome—a recessive form of LQTS accompanied by deafness. Their mother, a heterozygote, had a prolonged QTc interval without deafness. The variant was absent from 100 healthy control alleles. Variation at Glycine 168 is absent from the NHLBI Exome Sequencing Project database as of October 9, 2012. This database includes sequence information on approximately 4250 Caucasian and 2200 African American individuals. Nor is it present in 1000 Genomes as of October 9, 2012. It is listed in dbSNP as pathogenic: rs179489.

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