11-2583478-C-G

Variant names:

• chr11-2583478-C-G
• rs199472755
• NM_000218.3:c.965C>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.965C>G​(p.Thr322Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T322K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.42
• Publications: 20 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 19 ACMG points.

• PM1: In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 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 chr11-2583478-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53150.
• 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, 0.983
• PP5: Variant 11-2583478-C-G is Pathogenic according to our data. Variant chr11-2583478-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 200830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.965C>G	p.Thr322Arg	missense	Exon 7 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.965C>G	p.Thr322Arg	missense	Exon 7 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.695C>G	p.Thr232Arg	missense	Exon 8 of 17	NP_001393766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.965C>G	p.Thr322Arg	missense	Exon 7 of 16	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.584C>G	p.Thr195Arg	missense	Exon 7 of 16	ENSP00000334497.5
	KCNQ1	ENST00000713725.1		c.824C>G	p.Thr275Arg	missense	Exon 6 of 15	ENSP00000519029.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

May 17, 2013

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr322Arg (ACG>AGG): c.965 C>G in exon 7 of the KCNQ1 gene (NM_000218.2). While the Thr322Arg mutation in the KCNQ1 gene has not been reported to our knowledge, mutations affecting this same residue (Thr322Ala, Thr322Met, Thr322Lys) have been reported in association with LQTS (Choi G et al., 2004; Napolitano C et al., 2005; Hedley P et al., 2009). Additionally, mutations in nearby residues (Pro320Ser, Pro320Ala, Pro320His, Gly325Trp, Gly325Arg, Gly325Glu) have been reported in association with LQTS, supporting the functional importance of this residue and this region of the protein. Thr322Arg results in a semi-conservative amino acid substitution of a neutral, polar Threonine with a positively charged Arginine at a position that is conserved across species. Furthermore, Thr322Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Thr322Arg in the KCNQ1 gene has been observed in other unrelated individuals at GeneDx. The variant is found in LQT panel(s).

Long QT syndrome Pathogenic:1

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 322 of the KCNQ1 protein (p.Thr322Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 200830). 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.Thr322 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 17470695, 18400097, 19716085, 22949429, 23092362). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Cardiovascular phenotype Pathogenic:1

Feb 04, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T322R variant (also known as c.965C>G), located in coding exon 7 of the KCNQ1 gene, results from a C to G substitution at nucleotide position 965. The threonine at codon 322 is replaced by arginine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with long QT syndrome (Schwartz PJ et al. Eur Heart J. 2021 Dec;42(46):4743-4755; Ambry internal data). Based on internal structural analysis, this variant is predicted to be destabilizing (Long SB et al. Nature 2007;450(7168):376-82; Xu Yet al. Biophys. J. 2013;105(11):2461-73; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.90		Gain of MoRF binding (P = 0.0453)
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.97
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 0

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

Other links and lift over

dbSNP: rs199472755; hg19: chr11-2604708;