ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.424G>A (p.Gly142Ser) (rs120074193)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182118 SCV000234421 pathogenic not provided 2019-01-14 criteria provided, single submitter clinical testing The G269S variant has been reported several times in association with LQTS, and this variant was absent from more than 1,500 control alleles (Choi G et al., 2004; Ackerman M et al., 1999; Chen S et al., 2003). The G269S variant not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies demonstrated that the G269S variant may cause abnormal assembly and stability of the potassium channel (Verma R et al., 2009). Another missense variant affecting the same residue (G269D) and mutations in neighboring residues (L266P, I268S, G272D, L273F, L273R), have been reported in association with LQTS, further supporting the functional importance of this residue and region of the protein. Finally, G269S has also been observed in other unrelated individuals at GeneDx.
Invitae RCV000477568 SCV000543295 pathogenic Long QT syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 269 of the KCNQ1 protein (p.Gly269Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs120074193, ExAC 0.009%). This variant has been reported in many families affected with long QT syndrome and has been shown to segregate with the phenotype (PMID: 24184248, 15234419, 15176425, 18752142). ClinVar contains an entry for this variant (Variation ID: 3144). This variant identified in the KCNQ1 gene is located in the transmembrane S5 region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNQ1-topology. A different missense substitution at this codon (p.Gly269Asp) has been determined to be pathogenic (PMID: 9312006, 9386136, 10973849, 12051962, 12522251, 17470695). This suggests that the glycine residue is critical for KCNQ1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change affects protein stability and responsiveness (PMID: 20044973, 24184248). In summary, this variant has been found to segregate with long QT syndrome in several families and has a deleterious effect on a residue important for protein function. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762834 SCV000893193 pathogenic Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002562 SCV001160534 pathogenic not specified 2019-05-22 criteria provided, single submitter clinical testing The c.805G>A; p.Gly269Ser variant (rs120074193, ClinVarID 3144 ) was first reported in a 16-year-old asymptomatic boy, whose cousin passed out in a swimming pool due to a triggered cardiac event (Ackerman 1999). This patient's QT was measured at 470 ms. Since then, the p.Gly269Ser variant has been reported in patients with long QT syndrome, including at least four families, where the variant segregated with disease (Wu 2014, Fujii 2017). Additionally, other amino acid substitutions at this codon (p.Gly269Asp, p.Gly269Val) have been reported in individuals with LQTS and are considered pathogenic (Donger 1997, and ClinVar IDs: 3145 & 200899). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 269 is highly conserved in the transmembrane S5 domain, and functional studies demonstrate that the p.Gly269Ser variant causes a reduction in potassium ion current and protein stability (Wu 2014 and Verma 2010). Computational analyses by SIFT and PolyPhen-2 also predict that this variant is deleterious. Overall, this variant is considered to be pathogenic.
OMIM RCV000003294 SCV000023452 pathogenic Long QT syndrome 1 2002-09-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057765 SCV000089284 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:10560595;PMID:12205113;PMID:12702160;PMID:14678125;PMID:15466642;PMID:15840476;PMID:17905336;PMID:18752142;PMID:19716085;PMID:19808498;PMID:20044973;PMID:15234419;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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