ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.133G>A (p.Val45Met) (rs199472694)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414067 SCV000490579 uncertain significance not provided 2016-10-31 criteria provided, single submitter clinical testing The V172M variant has been published in association with LQTS, however, patient-specific clinical data, family history, or segregation studies were not provided (Zareba et al., 2003; Kapplinger et al., 2009). The V172M amino acid substitution occurs at a position that is conserved through mammals. Additionally, pathogenic missense variants in nearby residues (G168R, R174C/H ) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nonetheless, V172M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The V172M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, internal data from GeneDx indicate that this variant is present in Arab populations at a frequency greater than expected for LQTS, suggesting it may be a rare benign variant in this population. Finally, although this variant has been observed in several unrelated individuals tested for LQTS at GeneDx, segregation data is uninformative to date. Therefore, based on the currently available information, it is unclear whether V172M is pathogenic or a rare benign variant.
Ambry Genetics RCV000620765 SCV000735768 uncertain significance Cardiovascular phenotype 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764971 SCV000896148 uncertain significance 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
Invitae RCV000812759 SCV000953082 uncertain significance Long QT syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 172 of the KCNQ1 protein (p.Val172Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs199472694, ExAC 0.03%). This variant has been reported in one individual affected with long QT syndrome (LQTS) and in an individual with unexplained death (PMID: 14678125, 27650965). This variant has also been observed as homozygous in a patient with LQTS, however a second homozygous variant (p.Arg293Cys) was also identified in the KCNQ1 gene in this patient (PMID: 28944242). ClinVar contains an entry for this variant (Variation ID: 67078). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057687 SCV000089206 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:19716085). 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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