rs12720458

Positions:

• chr11-2585264-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1085A>G​(p.Lys362Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 U:1 O:1
• Conservation: PhyloP100: 8.70

Genes affected

KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 25) in uniprot entity KCNQ1_HUMAN there are 25 pathogenic changes around while only 1 benign (96%) in NM_000218.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 11-2585264-A-G is Pathogenic according to our data. Variant chr11-2585264-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2585264-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1085A>G	p.Lys362Arg	missense_variant	8/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1085A>G	p.Lys362Arg	missense_variant	8/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.704A>G	p.Lys235Arg	missense_variant	8/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.771+1719A>G		intron_variant		5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.588+1719A>G		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251350 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135876

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461718 Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 27, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 20, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielson syndrome (JLNS, MIM#220400) (OMIM, PMID: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is a more severe form of LQTS, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (10 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously observed twice in our LQTS patient cohort, and has been reported in both heterozygous and compound heterozygous state in patients with LQTS and JLNS, respectively (PMID: 19716085, 23392653). However, this variant has also been called an incidental finding in one patient with unexplained cardiac arrest and normal QTc at rest and during exercise (PMID: 35352813), and has been identified in three alleles in a cohort of >13k asymptomatic older individuals, classified as likely pathogenic (PMID: 34135346). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has also been shown to segregate with LQTS in two families (VCGS internal patients). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have demonstrated that this variant directly interacts with membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), which is required for Kv7 channel opening. However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification (PMID: 24947509). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 24, 2023	The KCNQ1 c.1085A>G (p.Lys362Arg) missense variant results in the substitution of lysine at amino acid position 362 with arginine. This variant has been identified in isolation and as part of a compound heterozygous pair in individuals with long QT syndrome and/or elongated QTc intervals (PMID: 15781747; 22949429; 23392653). A functional study conducted in non-human cells demonstrated that this variant impacts protein function (PMID: 26546361). This variant is located in a hotspot. This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.1085A>G (p.Lys362Arg) variant is classified as likely pathogenic for long QT syndrome. -

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCNQ1: PM1, PS4:Moderate, PM2:Supporting, PP3, PS3:Supporting -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 06, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Lys362Arg Based on the data reviewed below we consider this variant likely disease causing. The variant has been seen in at least 5 and as many as 8 unrelated cases. There is no segregation data available. Tester et al (2005) observed the variant in 2 of 541 unrelated patients referred for long QT genetic testing in a research laboratory at Mayo lead my Dr. Michael Ackerman. Individual phenotype is not reported, however the average QTc for the sample was 482 ms and 29% of subjects had a Schwartz score =4. The variant was reported in 5 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Kapa et al (2009) reported a Caucasian patient with this variant, however, that case may be redundant with the previously discussed cases since that sample was drawn from the Mayo and Familion cohorts with additional cases from a Dutch cohort. In another paper from Ackerman’s group the variant was reported in two patients with long QT syndrome who were compound heterozygotes but had normal hearing. In both patients the variant was in trans with p.Arg518Ter. Notably they are reported as unrelated families. It is unclear if these cases overlap with prior reports though to be conservative we will assume that they do. In a brief clinical case report on remarkable EKG findings, a team from Vanderbilt reported a woman with JLNS with a QTc over 900 ms in the post-partum period who had p.Ala314Val and p.Lys362Arg in KCNQ1 (Darbar et al 2005). One variant was inherited and the other was de novo (they don’t specify which). No information on the sequencing performed is provided. Given the availability of long QT genetic testing at the time it may have been done either by Dr. Ackerman’s research lab (i.e. Tester et al 2005), another research lab, or by Familion/PGxHealth (Kapplinger et al 2009), so there is again potential for overlap with previous cases. PolyPhen-2 predicts the variant to be probably damaging and mutation taster predicts the variant to be disease causing. The lysine at codon 362 is conserved across species, with the exception of elegans, where there is an arginine. The neighboring residues are highly or completely conserved. The variant is in the c-terminal region of the protein. I could find no other variants at the same codon. Variants in nearby codons have been reported in association with long QT syndrome: p.Arg360Gly (Moss et al 2007), p.Gln357His (Moss et al 2007), p.Gln357Arg (Chen et al 2003, Boulet et al 2006), p.Arg360Tyr (Napolitano et al 2005), p.Arg360Met (Kapplinger et al 2009), p.His363Asn (Struijk et al 2006, Hedley et al 2009), p.Asn365His (Kapplinger et al 2009), p.Arg366Gln (Tanaka et al 1997, Splawski et al 2000), and p.Gln367His (Crotti et al 2007). The variant is listed in dbSNP (rs12720458), with data submitted by PharmGKB. Frequency data on HapMap samples is listed (CEU: 0/29, CHB: 0/44, JPT: 0/43, YRI: 0/29). 1 of 138 individuals in a sample named “PA130021341”. The nature of that sample is unclear and instructions provided to get more information didn’t yield the information. The variant is listed in 1000 genomes as a variant imported from dbSNP (opposed to one observed in the 1000 genomes dataset). There is no variation at codon 362 in the NHLBI ESP, which currently includes variant calls from ~6500 in -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2024	Observed in two unrelated families with LQTS that also harbored another pathogenic KCNQ1 variant on the opposite allele (in trans), yet two compound heterozygous individuals did not have a history of hearing loss (PMID: 23392653); Reported in individuals with Jervell-Lange Nielsen syndrome referred for genetic testing at GeneDx and in published literature (PMID: 15781747); Identified in a patient with cardiomyopathy and history of unexplained cardiac arrest but normal QTc interval; the authors suggest this is an incidental finding and the cardiac arrest is due to cardiomyopathy (PMID: 35352813); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in multiple unrelated patients with LQTS referred for genetic testing at GeneDx and in published literature (PMID: 15840476, 23392653, 27831900, 36136372); This variant is associated with the following publications: (PMID: 19716085, 19841300, 22949429, 25525159, 15840476, 27831900, 29197658, 30755392, 30609406, 26546361, 31447099, 22581653, 31589614, 34135346, 33087929, 34319147, 23631430, Sanatani2022[Article], 24947509, 24077912, 36136372, 23392653, 15781747, 35352813) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 31, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2021	- -

Long QT syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 12, 2024	The c.1085A>G (p.Lys362Arg) variant in the KCNQ1 gene has been identified in heterozygous status in at least four individuals with Long QT syndrome (LQTS) (PMID: 19841300, 22949429, 27831900, 32893267); in compound heterozygous status with another pathogenic variant (p.Ala341Val) in an individual with Jervell-Lange Nielsen syndrome (PMID: 15781747); in compound heterozygous status with a well-established pathogenic variant (p.Arg518*) in two unrelated individuals with severe LQTS phenotype and segregated with prolonged QT in their affected relatives who are carriers of p.Lys362Arg (PMID: 23392653); and in heterozygous status in an individual with cardiomyopathy presented with a left bundle branch block and history of unexplained cardiac arrest, but normal QTc interval in the proband and his sister who also carried p.Lys362Arg (PMID: 35352813). This variant has also been observed in seven individuals who have been referred for LQTS testing, however, their detailed clinical information is not available (PMID: 19716085, 15840476). This variant was observed in 3 alleles from a study of 13,131 asymptomatic individuals aged 70 years and older without a history of cardiovascular events, suggesting incomplete penetrance (PMID: 34135346). In vitro functional studies have shown that this variant affects current amplitude in vitro and disrupts the potassium channel regulation in renal ciliogenesis (PMID:24947509, 26546361). In-silico computational prediction tools suggest that the p.Lys362Arg variant may have deleterious effect on the protein function (REVEL score: 0.964). This variant is found to be rare (10/251350) in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several (11) submitters in the ClinVar database (ClinVar ID: 52953). Therefore, the c.1085A>G (p.Lys362Arg) variant in the KCNQ1 gene is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 362 of the KCNQ1 protein (p.Lys362Arg). This variant is present in population databases (rs12720458, gnomAD 0.008%). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 15781747, 15840476, 22949429; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 52953). 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: 24947509, 26546361). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 02, 2020	Variant summary: KCNQ1 c.1085A>G (p.Lys362Arg) results in a conservative amino acid change located in the Ion transport domain (IPR005821) 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 251350 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in KCNQ1 causing Long QT Syndrome (4e-05 vs 8.3e-05), allowing no conclusion about variant significance. c.1085A>G has been reported in the literature in heterozygous individuals with Long QT syndrome and in patients undergoing genetic testing for the same phenotype (Kapa_2009, Kapplinger_2009, Natarajan_2016). The variant was also identified in individuals affected with Long QT syndrome with intact auditory phenotype (Giudicessi_2013) and Jervell-Lange-Nielsen syndrome in compound heterozygous state along with other pathogenic KCNQ1 variants. These data indicate that the variant is likely to be associated with disease. Experimental evidence suggests the variant may impact channel function (Slaats_2015). Six ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic (n=4) or pathogenic (n=2). In addition, several other variants affecting the nearby codons (p.R360G, p.R360M, p.R360T,p.H363N, p.N365H) have been reported (HGMD database), suggesting this area might be a mutational hotspot. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 29, 2016	- -

Congenital long QT syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 03, 2020	The p.Lys362Arg variant in KCNQ1 has been reported in the heterozygous state in at least 4 individuals with long QT syndrome (LQTS), in the compound heterozygous state with another well-established pathogenic variant in 2 individuals with an early-onset, more severe LQTS phenotype without hearing loss and segregated with prolonged QT in 2 affected relatives from 2 families (Kapa 2009 PMID: 19841300, Guidicessi 2012 PMID: 22949429, Giudicessi 2013 PMID: 23392653, GeneDx pers. comm., Invitae pers. comm., LMM data). It has also been reported in the compound heterozygous state in 1 individual with Jervell-Lange-Nielsen syndrome (JLNS; Darbar 2005 PMID: 15781747). Additionally, it has been identified in at least 5 individuals that have been referred for long QT syndrome (LQTS) testing; however, their detailed clinical information was not available (Tester 2005 PMID: 15840476, Kapplinger 2009 PMID: 19716085). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 52953) and has been identified in 0.008% (9/113664) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Lys362Arg variant may impact the protein (Slaats 2015 PMID: 26546361, Eckey 2014 PMID: 24947509) and computational prediction tools and conservation analysis suggest that the p.Lys362Arg variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Lys362Arg variant is likely pathogenic for autosomal dominant LQTS. In the presence of another pathogenic variant in trans (on the other copy of the KCNQ1 gene), this variant may also cause a more severe form of LQTS with an earlier age of onset. ACMG/AMP Criteria applied: PM3_Strong; PP3; PS3_Supporting. -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 18, 2023

The c.1085A>G p.(Lys362Arg) variant identified in the KCNQ1 gene has previously been reported in the literature in at least 6 individuals with long QT syndrome [PMID: 34798354]. This variant has also been reported at the compound heterozygous state in 3 unrelated individuals with autosomal recessive Jervell-Lange-Nielsen syndrome; one heterozygous carrier was reported with QT prolongation on ECG, whereas another carrier had a normal QT interval [PMID: 15781747; 23392653]. This variant has been reported in ClinVar [ClinVar ID: 52953] as Variant of Uncertain Significance (2 submissions), Likely Pathogenic (8 submissions) or Pathogenic (3 submissions). The c.1085A>G variant is observed in 9 alleles (~0.003 % minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1085A>G p.(Lys362Arg) variant in KCNQ1 is located in exon 8 of this 16-exon gene, and predicted to replace an evolutionarily conserved lysine amino acid with arginine at position 362 in the c-terminal region of the encoded protein. Functional studies have shown that this missense variant affects the potassium channel regulation in renal ciliogenesis and that is involved in anionic phospholipids binding. However, these studies are not conclusive regarding the potential effect of this variant on the cardiac ion channel [PMID: 21084310, 24947509, 26546361]. In silico predictions are in favor of damaging effect for KCNQ1 p.(Lys362Arg) [REVEL = 0.964)]. Variants nearby p.(Lys362Arg) residue within the C-terminus domain have been reported in the literature in association with long QT syndrome [PMID:19716085, 34505893,] and ClinVar [ClinVar ID: 52955]. Based on available evidence this c.1085A>G p.(Lys362Arg) variant identified in the KCNQ1 gene is reported as Likely Pathogenic. -

Polyhydramnios;C0235659:Decreased fetal movement;C0240635:High palate;C0426440:Enlarged naris;C0431352:Secondary microcephaly;C0948163:Abnormal cerebral white matter morphology;C1845123:Generalized neonatal hypotonia;C1858120:Generalized hypotonia;C2267233:Neonatal hypotonia;C2677180:Primary microcephaly;C4021637:Abnormal nostril morphology;C4021770:Toe clinodactyly;C4024923:Diffuse white matter abnormalities Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

KCNQ1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a heterozygous change in several unrelated individuals affected with long QT syndrome (PMID: 15840476, 22949429). It has also been reported in the compound heterozygous state in 1 individual with Jervell-Lange-Nielsen syndrome (PMID: 15781747). Missense variation is an established mechanism of disease for KCNQ1-related disorders (HGMD). Experimental studies have shown that the presence of this variant leads to an abnormal KCNQ1 channel (PMID: 24947509, 26546361). The c.1085A>G (p.Lys362Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/251350) and thus is presumed to be rare. The c.1085A>G (p.Lys362Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1085A>G (p.Lys362Arg) variant is classified as Likely Pathogenic. -

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551647:Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Nov 27, 2019

The p.Lys362Arg variant in the KCNQ1 gene is a heterozygous missense variant, which results in the substitution of the highly conserved lysine residue at the 362 position to arginine. This variant localizes to coding exon 8 of the KCNQ1 gene and is within the helical transmembrane region of the protein. This variant is predicted to be deleterious and damaging to protein structure and/or function based on in silico analyses (damaging by SIFT, probably damaging by PolyPhen2).This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (10/251,350), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in the heterozygous state in individuals with LQTS (PMIDs: 15840476, 19841300, 19716085, 22949429, and 27831900). This variant has also been seen in the compound heterozygous state in three individuals with autosomal recessive JLNS with or without hearing loss ((PMIDs: 23392653 and 15781747). -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 28, 2023

This missense variant replaces lysine with arginine at codon 362 of the KCNQ1 protein. This variant is found within a highly conserved region (a.a.349-391) of the C-terminal cytoplasmic domain. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant affects the potassium channel function (PMID: 24947509, 26546361). This variant has been reported in at least seven unrelated heterozygous individuals affected with or suspected of having long QT syndrome (PMID: 15840476, 19716085, 19841300, 22949429, 32893267, 34404389, 36102233, ClinVar SCV000073970.6). This variant has also been observed in an individual affected with cardiac arrest and cardiomyopathy (PMID: 35352813) and in several asymptomatic individuals as well (PMID: 23392653, 34135346, 35352813). This variant has been reported in compound heterozygous state with a pathogenic variant in the same gene in an individual affected with Jervell and Lange-Nielsen syndrome (PMID: 15781747), as well as in two unrelated individuals affected with severe, early-onset long QT syndrome (PMID: 23392653). This variant has been identified in 10/251350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, flagged submission

clinical testing

Ambry Genetics

Oct 31, 2022

The c.1085A>G (p.K362R) alteration is located in exon 8 (coding exon 8) of the KCNQ1 gene. This alteration results from a A to G substitution at nucleotide position 1085, causing the lysine (K) at amino acid position 362 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.86
MVP		0.98
MPC		1.0
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.89
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12720458; hg19: chr11-2606494;