rs199472756

Variant names:

• chr11-2583486-G-A
• rs199472756
• NM_000218.3:c.973G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2583486-G-A
• chr11-2583486-G-C
• chr11-2583486-G-T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.973G>A​(p.Gly325Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G325E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 9.36
• Publications: 16 publications found

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]

KCNQ1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS1: Transcript NM_000218.3 (KCNQ1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2583487-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 200831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 11-2583486-G-A is Pathogenic according to our data. Variant chr11-2583486-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 53152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.973G>A	p.Gly325Arg	missense_variant	Exon 7 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.973G>A	p.Gly325Arg	missense_variant	Exon 7 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727176

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0240912), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000101 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 26, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic (ClinVar Variant ID# 53152; ClinVar); Published functional studies demonstrate that G325R leads to non-functional channels and suppresses wild-type current (Aidery et al., 2012; Burgess et al., 2012); This variant is associated with the following publications: (PMID: 9024139, 19841300, 17470695, 22949429, 21118729, 19716085, 15234419, 9386136, 14998624, 23092362, 23098067, 10973849, 26669661, 28292826, 22456477, 17905336, 11668638, 22581653, 29447731, 23000022, 32383558, 30123799) -

Jan 11, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.Gly325Arg This variant has been reported in at least 13 unrelated cases with Long QT syndrome. There weak segregation data on the variant. The variant is also referred to as p.Gly198Arg (NP_861463.1) and p.Gly196Arg (older numbering system?). Tanaka et al (1997) reported p.Gly196Arg in 1 out of 32 Japanese families with Long QT. Later papers reporting on p.Gly325Arg refer to Tanaka et al, suggesting this is the same variant. Several papers on KCNQ1 from 1996 and 1997 appear to use an older numbering system. The case reported by Tanaka et al (1997) may overlap with one later reported by Shimizu et al (2004) since both were recruited from throughout Japan. Donger et al (1997) reported the variant in 1 out of 20 French families with long QT. Within this family there were 5 carriers, 4 of which had a syncopal event before 10 years of age. Individual QTc was not reported, mean QTc for the family was 460 ms. Splawski et al (2000) later reported of 2 additional cases with the variant and long QT syndrome in a cohort recruited from North America and Europe (likely Italian since Priori is the only European author). Larsen et al (2001) report this variant in a genetic testing methods paper noting that the patients were Danish. Lupoglazoff et al (2004) genotyped neonates with ventricular rates less than 110 beats per minute, p.Gly325Arg was identified in 1 female with a QTc of 550ms and a fetal ventricular rate at 90 beats per minute. She was asymptomatic at age 2. This study population was recruited in France. Chung et al (2007) identified the variant in 1 out of 84 unrelated individuals with long QT from New Zealand and Australia. The patient was a 53 year old female of European descent with a QTc of 520ms. The variant was reported in 6 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his lab and from the Familion cohort. 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). Aidery et al (2012) reported a patient with long QT and p.Gly325Arg; the patient was a female of German ancestry who was diagnosed at age 5 (QTc 480 ms). She had a history of VSD with spontaneous closure in early infancy and exhibited onychondystropy on hands and feet. She was asymptomatic at time of publication. Moss et al (2007) include this variant in their study on genotype-phenotype correlations, however the sample was drawn from the international registry, the Dutch registry, and the Japanese registry, so these cases may overlap with Shimizu et al (2004), Tanaka et al (1997), Kapa et al (2009) and Splawski et al (2000). Burgess et al (2012) report on a pool of patients with this variant. Many, and possibly all, of the cases likely overlap with prior reports given the overlap in authors. However, they provide individual and family level data in the supplement that is helpful. They report a total of 11 unrelated cases with segregation in multiple families; in at least 3 families the variant appears to segregate with disease in at least 2 individuals. This is a semi conservative amino acid change with a non polar, neutral Glycine replaced with a polar, positive Arginine. This variant is located in the S6 pore domain of the potassium channel. In silico (S -

Long QT syndrome Pathogenic:3

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 325 of the KCNQ1 protein (p.Gly325Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 21118729, 22456477, 22949429, 23000022, 23092362, 23158531, 26669661). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53152). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 23000022, 23092362). For these reasons, this variant has been classified as Pathogenic. -

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PS1, PS4_Moderate, PM1_Strong, PM2, PP3 -

Aug 28, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNQ1 c.973G>A (p.Gly325Arg) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes. c.973G>A has been reported in the literature in numerous individuals affected with LQTS, including a study that found the variant in 11 families in which the variant segregated with prolonged QTc in 15 individuals (Burgess_2012). Functional studies have reported the variant to lead to non-functional channel, resulting in a dominant negative suppression of wild-type current (Burgess_2012, Aidery_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Long QT syndrome 1 Pathogenic:1

Feb 07, 2020

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Nov 22, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G325R pathogenic mutation (also known as c.973G>A), located in coding exon 7 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 973. The glycine at codon 325 is replaced by arginine, an amino acid with dissimilar properties. This alteration (and another nucleotide change (c.973G>C) resulting in the same amino acid substitution) has been detected in multiple unrelated individuals reported to have long QT syndrome or prolonged QTc interval and has been reported to segregate with prolonged QTc intervals in families (Tanaka T et al. Circulation. 1997;95:565-7 (reported as G196R, GGG to AGG); Donger C et al. Circulation. 1997;96:2778-81; Splawski I et al. Circulation. 2000;102:1178-85; Lupoglazoff JM et al. J Am Coll Cardiol. 2004;43:826-30; Shimizu WJ et al. Am Coll Cardiol. 2004;44(1):117-25; Moss AJ et al. Circulation. 2007;115:2481-9; Kapa S et al. Circulation. 2009;120:1752-60; Crotti L et al. J Am Coll Cardiol. 2012;60(24):2515-24; Burgess DE et al. Biochemistry. 2012;51:9076-85). In addition, in vitro functional studies report this alteration to result in loss of function and dominant negative suppression of wild type channel current (Aidery P et al. Gene. 2012;511:26-33; Burgess DE et al. Biochemistry. 2012;51:9076-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Congenital long QT syndrome Other:1

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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9024139;PMID:9386136;PMID:10973849;PMID:11668638;PMID:14998624;PMID:17905336;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.;.
PhyloP100		9.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.5	D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;D
Vest4		1.0
MutPred		0.98		Gain of MoRF binding (P = 0.0599);.;.;
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.98
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs199472756; hg19: chr11-2604716;