Submissions for variant NM_000218.3(KCNQ1):c.437A>G (p.Glu146Gly)

gnomAD frequency: 0.00001  dbSNP: rs914460959

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482770	SCV000565093	uncertain significance	not provided	2022-06-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Functional studies suggest that this variant has a peak current density and Tdeact parameters close to the wild type (Phul et al., 2022); This variant is associated with the following publications: (PMID: 32009526, 35442947, 26734131)
Invitae	RCV001039538	SCV001203070	likely pathogenic	Long QT syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 146 of the KCNQ1 protein (p.Glu146Gly). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 26734131, 32009526). This variant is also known as c.56A>G (p.Glu19Gly). ClinVar contains an entry for this variant (Variation ID: 418272). 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 with a positive predictive value of 95%. This variant disrupts the p.Glu146 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248899	SCV001422583	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Glu146Gly variant in KCNQ1 has not been previously reported in individuals with Long QT Syndrome but has also been reported likely pathogenic in ClinVar by GeneDx (Variation ID: 418272). This variant has been identified in 0.003266% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs914460959). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease with clinical variability. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Glu146Lys, has been reported in at least one individual with Long QT Syndrome in the literature and ClinVar (PMID: 16414944; Variation ID: 53043). In summary, the clinical significance of the p.Glu146Gly variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015).
Ambry Genetics	RCV002329140	SCV002633006	uncertain significance	Cardiovascular phenotype	2023-08-21	criteria provided, single submitter	clinical testing	The p.E146G variant (also known as c.437A>G), located in coding exon 2 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 437. The glutamic acid at codon 146 is replaced by glycine, an amino acid with similar properties. This alteration was reported in an individual who experienced exercise induced sudden cardiac arrest and was diagnosed with long QT syndrome (Sandhu A et al. Clin Case Rep, 2015 Dec;3:971-4). This variant was later reported in a female with a prolonged QTc value; however, additional clinical details were not provided (Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). This amino acid position is highly 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.