Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV001843225 | SCV001350876 | uncertain significance | Cardiac arrhythmia | 2023-05-16 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with glutamic acid at codon 635 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNQ1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Invitae | RCV001360633 | SCV001556559 | uncertain significance | Long QT syndrome | 2023-10-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 635 of the KCNQ1 protein (p.Gly635Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 923807). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. 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. |
Ambry Genetics | RCV002411701 | SCV002722662 | uncertain significance | Cardiovascular phenotype | 2023-03-30 | criteria provided, single submitter | clinical testing | The p.G635E variant (also known as c.1904G>A), located in coding exon 16 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1904. The glycine at codon 635 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Fulgent Genetics, |
RCV002480612 | SCV002790271 | uncertain significance | Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2 | 2021-08-30 | criteria provided, single submitter | clinical testing | |
Petrovsky National Research Centre of Surgery, |
RCV003163439 | SCV003842264 | uncertain significance | Polymorphic ventricular tachycardia | 2023-02-15 | criteria provided, single submitter | clinical testing | We observed a c.1904G>A (p.G635E) genetic variant in the KCNQ1 gene on WES data in a 48-y.o. male proband, manifested with cardiac arrhythmia (polymorphic PVCs, episode of non- sustained VT). The proband also carried the additional variant of unknown clinical significance in the MYBPC3 gene - c.3336G>T (p.W1112C) in heterozygous state (also on WES data). The c.1904G>A (p.G635E) genetic variant in the KCNQ1 gene is not observed at significant frequency in large population cohorts (gnomAD v3.1.2). ClinVar contains an entry for this variant (Variation ID: 923807). The PM1 criterion is «supporting» according to Walsh R. et al. (PMID: 32893267). Multiple in silico resources predict benign effect of this variant. However, in the absence of the functional studies, we could only classify the c.1904G>A (p.G635E) genetic variant as a variant of uncertain clinical significance. |