Submissions for variant NM_000218.3(KCNQ1):c.860C>A (p.Ala287Glu)

gnomAD frequency: 0.00005  dbSNP: rs199472735

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150869	SCV000198429	uncertain significance	not specified	2019-01-31	criteria provided, single submitter	clinical testing	The p.Ala287Glu variant in KCNQ1 has been reported as causative for long QT syndrome in one study; however, the number of probands with the variant and the number of segregations in affected family members is not stated (Napolitano 2005). This variant has not been reported in individuals with hearing loss or Jervell and Lange-Nielsen syndrome, but also has not been identified in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala287Glu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, additional data is needed to determine the clinical significance of this variant.
Ambry Genetics	RCV000618222	SCV000737796	uncertain significance	Cardiovascular phenotype	2016-11-02	criteria provided, single submitter	clinical testing	The p.A287E variant (also known as c.860C>A), located in coding exon 6 of the KCNQ1 gene, results from a C to A substitution at nucleotide position 860. The alanine at codon 287 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant was previously reported in a long QT syndrome cohort; however, clinical details were limited (Napolitano C et al. JAMA. 2005;294:2975-80). In functional in vitro analyses, this variant demonstrated increased peak current amplitudes, an effect typically associated with short QT syndrome (Rothenberg I et al. HeartRhythm Case Rep. 2016;DOI:http://dx.doi.org/10.1016/j.hrcr.2016.08.015). Another alteration involving the same amino acid position, p.A287T (c.859G>A), was detected in a patient with short QT syndrome and two unaffected relatives (Rothenberg I et al, 2016) in addition to other long QT syndrome cohorts, however, with limited clinical details (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61). This p.A287E variant was previously reported in the SNPDatabase as rs199472735. Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (3/105050). This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV001841655	SCV000904481	uncertain significance	Cardiac arrhythmia	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glutamic acid at codon 287 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in increased peak current amplitudes of the ion channels (PMID: 284917516). This variant has been reported in individuals affected with or suspected of long QT syndrome (PMID:16414944, 31737537). This variant has been identified in 13/250332 chromosomes 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	RCV001316443	SCV001507062	uncertain significance	Long QT syndrome	2022-06-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 287 of the KCNQ1 protein (p.Ala287Glu). This variant is present in population databases (rs199472735, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 16414944, 31737537). ClinVar contains an entry for this variant (Variation ID: 53118). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 28491751). 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.
GeneDx	RCV001588869	SCV001824021	uncertain significance	not provided	2019-12-27	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31737537, 32048431, 29197658, 16414944, 22581653, 23631430, 28491751)
CeGaT Center for Human Genetics Tuebingen	RCV001588869	SCV002585268	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057782	SCV000089301	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:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.