Submissions for variant NM_000218.3(KCNQ1):c.584G>A (p.Arg195Gln)

gnomAD frequency: 0.00008  dbSNP: rs138362632

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000057714	SCV000055277	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000057714	SCV000234390	uncertain significance	not provided	2023-04-06	criteria provided, single submitter	clinical testing	Observed in association with LQTS in the published literature (Clemens et al., 2017) as well as identified in ostensibly healthy control populations (Kapa et al., 2009; Giudicessi et al., 2012); Published in vitro functional studies suggest a damaging effect (Zaydman et al., 2013, Vanoye et al., 2018); nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22949429, 25564853, 25559286, 25649125, 19841300, 23861362, 30571187, 32797034, 31229680, 29197658, 23861489, 35442947, 36007526)
Invitae	RCV000231075	SCV000283886	uncertain significance	Long QT syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 195 of the KCNQ1 protein (p.Arg195Gln). This variant is present in population databases (rs138362632, gnomAD 0.006%). 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: 67088). 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%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 23861489, 30571187). 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	RCV000618352	SCV000738208	uncertain significance	Cardiovascular phenotype	2019-11-25	criteria provided, single submitter	clinical testing	The c.584G>A (p.R195Q) alteration is located in exon 3 (coding exon 3) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 584, causing the arginine (R) at amino acid position 195 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001841688	SCV000905123	uncertain significance	Cardiac arrhythmia	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 195 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). Experimental studies have shown that this variant reduces the whole-cell current amplitude of the channel (PMID: 23861489) and suppressed the current-enhancing effect of a KCNQ1 activator (PMID: 25564853). This variant has been reported in an individual suspected of having epilepsy (PMID: 31696929) and in two control subjects (PMID: 19841300, 22949429). This variant has also been identified in 11/280490 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193175	SCV001361859	uncertain significance	not specified	2019-02-05	criteria provided, single submitter	clinical testing	Variant summary: The variant, KCNQ1 c.584G>A (p.Arg195Gln) results in a conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277966 control chromosomes (gnomAD and Kapa_2009). This frequency is not higher than expected for a pathogenic variant in KCNQ1 causing Arrhythmia (4e-05 vs 0.0001), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.584G>A in individuals affected with Arrhythmia has been reported. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated decreased whole-cell current amplitudes in Xenopus oocytes, however these results do not allow convincing conclusions about the variant effect (Zaydman_2013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2X uncertain significance, and 1X Likely Pathogenic). Based on the evidence outlined above, the variant was classified as uncertain significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000057714	SCV002501111	uncertain significance	not provided	2022-01-12	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335087	SCV004046080	likely pathogenic	KCNQ1-related disorder		criteria provided, single submitter	clinical testing	This variant is also known as c.203G>A (p.Arg68Gln) in an alternate KCNQ1 transcript (NM_181798.1). This variant has been previously reported in individuals with Long QT syndrome (LQTS; PMID: 29197658). The c.584G>A (p.Arg195Gln) variant is located in a mutational hotspot for pathogenic variations associated with LQTS (PMID: 29851656). This change is predicted by multiple in silico tools to have a deleterious effect on protein function, and functional studies have shown that it alters the protein's voltage-gating activity (PMID: 23861489). Pathogenic missense variants are an established mechanism of disease for KCNQ1-related disorders (PMID: 29532034, 30571187, 29851656, 29197658, 19632626), including a missense variant at the same amino acid residue reported in LQTS (Arg159Pro; PMID: 29532034, 30571187). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (11/280490) and thus is presumed to be rare. Based on the available evidence, the c.584G>A (p.Arg195Gln) variant is classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003335087	SCV004113231	uncertain significance	KCNQ1-related disorder	2023-05-01	criteria provided, single submitter	clinical testing	The KCNQ1 c.584G>A variant is predicted to result in the amino acid substitution p.Arg195Gln. This variant has been previously observed in a cohort of individuals with cardiomyopathy (reported as “benign polymorphism/score 2” in Supplementary table 3, Ng et al. 2013. PubMed ID: 23861362), and a healthy control from a cohort of individuals participating in a case-control study of long QT syndrome (Table S1, Kapa et al. 2009. PubMed ID: 19841300). In vitro functional studies and/or in silico predicting models report conflicting interpretations regarding this variant’s pathogenicity (Kernik et al. 2020. PubMed ID: 32797034; Vanoye et al. 2018. PubMed ID: 30571187; Zaydman et al. 2013. PubMed ID: 23861489). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2591964-G-A). Based on gnomAD frequency data, a recent study considered this variant as statistically too common to be a LQT1-causative variant and recommended downgrading it (Clemens et al. 2018. PubMed ID: 29197658). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000231075	SCV004838764	uncertain significance	Long QT syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 195 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). Experimental studies have shown that this variant reduces the whole-cell current amplitude of the channel (PMID: 23861489) and suppressed the current-enhancing effect of a KCNQ1 activator (PMID: 25564853). This variant has been reported in an individual suspected of having epilepsy (PMID: 31696929) and in two control subjects (PMID: 19841300, 22949429). This variant has also been identified in 11/280490 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057714	SCV000089233	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300).