ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.644T>G (p.Val215Gly)

gnomAD frequency: 0.00001  dbSNP: rs368011737
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000559784 SCV000627396 likely pathogenic Long QT syndrome 2022-10-31 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 30571187). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. ClinVar contains an entry for this variant (Variation ID: 456868). This missense change has been observed in individual(s) with long QT syndrome (Invitae). This variant is present in population databases (rs368011737, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 215 of the KCNQ1 protein (p.Val215Gly). This variant disrupts the p.Val215 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 19841300, 20421371, 23098067, 23392653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000764972 SCV000896149 uncertain significance Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV004023761 SCV005033109 uncertain significance Cardiovascular phenotype 2024-02-07 criteria provided, single submitter clinical testing The p.V215G variant (also known as c.644T>G), located in coding exon 4 of the KCNQ1 gene, results from a T to G substitution at nucleotide position 644. The valine at codon 215 is replaced by glycine, an amino acid with dissimilar properties. Functional analysis suggests this alteration causes a moderate decrease in channel current; however, the physiological relevance of this result is unclear (Vanoye CG et al. Circ Genom Precis Med, 2018 Nov;11:e002345). This alteration has been reported in an ostensibly healthy control (Kapa S et al. Circulation, 2009 Nov;120:1752-60). This variant has also been reported in a sudden unexplained death cohort (Huang J et al. J Forensic Sci, 2015 Mar;60:351-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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