ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.1559T>G (p.Met520Arg) (rs199473479)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621710 SCV000738010 likely pathogenic Cardiovascular phenotype 2018-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Deficient protein function in appropriate functional assay(s)
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057597 SCV000089116 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:17482572;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.
GeneDx RCV000182199 SCV000234502 likely pathogenic not provided 2015-11-17 criteria provided, single submitter clinical testing The M520R likely pathogenic variant in the KCNQ1 gene has been reported in association with LQTS (Schmitt N et al., 2007; Kapplinger J et al., 2009; Kapa et al., 2009; Giudicessi et al., 2012). Schmitt et al. (2007) identified M520R in multiple individuals of one family with prolonged QT intervals. This study also noted that M520R leads to an intracellular trafficking defect and channel loss of function, resulting in haploinsufficiency (Schmitt et al., 2007). Additionally, the M520R variant was observed in at least 4 unrelated individuals with LQTS and it was absent from over 2,600 control alleles (Kapplinger et al, 2009; Kapa et al., 2009; Giudicessi et al., 2012). The M520R variant also was 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. Additionally, missense variants in nearby codons (R518Q, R518G, R518P, R519C, Y522S, V524G, A525T, A525V) have been reported in association with LQTS, further supporting the functional importance of this region of the protein (Stenson et al., 2014).Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000045999 SCV000074012 pathogenic Long QT syndrome 2017-03-14 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 520 of the KCNQ1 protein (p.Met520Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (rs199473479, ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (PMID: 22949429, 22456477, 26669661), and has been shown to segregate with the phenotype in a family (PMID: 17482572). ClinVar contains an entry for this variant (Variation ID: 52993). This variant identified in the KCNQ1 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). Experimental studies have shown that this missense change causes a KCNQ1 trafficking defect in vitro (PMID: 17482572). For these reasons, this variant has been classified as Pathogenic.

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