11-2583471-C-T

Variant names:

• chr11-2583471-C-T
• rs199472753
• NM_000218.3:c.958C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS4_Supporting PM2_Supporting PP3 PM1

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.958C>T is a missense variant predicted to cause substitution of proline by serine at amino acid 320 (p.Pro320Ser). This variant is rare and has been reported in 2 apparently unrelated probands affected with long QT syndrome 1 (PS4_Supporting; PMID:23392653, PMID:32383558). This variant is absent in gnomAD v.2.1.1, but present in gnomAD v4.1.0 at a maximum allele frequency of 0.0000008994, with 1 allele / 1,111,812 total alleles in the European Non-Finnish population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). This variant is a missense substitution within the pore helix consisting of amino acids 300 to 320, which is a well-characterized functional domain required for the channel function and selectivity filter of KCNQ1 (PMID:15649981), and has been confirmed to show an absence of likely benign or benign variants listed in gnomAD (PM1). The computational predictor REVEL gives a score of 0.98, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance due to insufficient evidence for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS4_Supporting, PM2_Supporting, PM1, PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA008910/MONDO:0100316/112

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:6 U:2 O:1
• Conservation: PhyloP100: 7.42
• Publications: 12 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: Uncertain_significance. The variant received 5 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.958C>T	p.Pro320Ser	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.958C>T	p.Pro320Ser	missense_variant	Exon 7 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461570 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727086

African (AFR) AF: 0.00 AC: 0 AN: 33476

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: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111812

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:6 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Mar 19, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_Moderate, PM2, PM5, PP3 -

Nov 15, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); At the protein level, silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar (ClinVar Variant ID# 67130; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19716085, 22581653, 23392653, 19540844, 26669661, 29033053, 27041150, 32383558) -

Long QT syndrome Pathogenic:2

Jun 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 320 of the KCNQ1 protein (p.Pro320Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 23392653; Invitae). ClinVar contains an entry for this variant (Variation ID: 67130). 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.Pro320 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19540844, 22949429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 13, 2025

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.958C>T (p.Pro320Ser) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 253994 control chromosomes. c.958C>T has been observed in multiple individuals affected with Long QT Syndrome (Giudicessi_2013, Westphal_2020, Schwartz_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23392653, 19716085, 34505893, 32383558). ClinVar contains an entry for this variant (Variation ID: 67130). Based on the evidence outlined above, the variant was classified as pathogenic. -

Long QT syndrome 1 Pathogenic:1 Uncertain:1

Nov 29, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS4_MOD, PM1, PM5, PM2_SUP, PP3 -

Jul 01, 2025

ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

NM_000218.3(KCNQ1):c.958C>T is a missense variant predicted to cause substitution of proline by serine at amino acid 320 (p.Pro320Ser). This variant is rare and has been reported in 2 apparently unrelated probands affected with long QT syndrome 1 (PS4_Supporting; PMID: 23392653, PMID: 32383558). This variant is absent in gnomAD v.2.1.1, but present in gnomAD v4.1.0 at a maximum allele frequency of 0.0000008994, with 1 allele / 1,111,812 total alleles in the European Non-Finnish population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001 (PM2_Supporting). This variant is a missense substitution within the pore helix consisting of amino acids 300 to 320, which is a well-characterized functional domain required for the channel function and selectivity filter of KCNQ1 (PMID: 15649981), and has been confirmed to show an absence of likely benign or benign variants listed in gnomAD (PM1). The computational predictor REVEL gives a score of 0.98, which is above the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 and predicts a damaging effect on KCNQ1 function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance due to insufficient evidence for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: PS4_Supporting, PM2_Supporting, PM1, PP3. (VCEP specifications version 1.0.0; date of approval 03/04/2025). -

Cardiovascular phenotype Pathogenic:1

Jun 05, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P320S variant (also known as c.958C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 958. The proline at codon 320 is replaced by serine, an amino acid with similar properties, and is located in the pore domain. This variant was detected in an individual with prolonged QT, who also had an additional KCNQ1 variant detected, as well as in her affected son who had prolonged QT and only this variant (Giudicessi JR et al. Circ Cardiovasc Genet, 2013 Apr;6:193-200). In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data, Sun J et al. Cell, 2017 Jun;169:1042-1050.e9). Alternate amino acid substitutions at this codon, p.P320A and p.P320H, have also been reported in LQTS cohorts, and functional studies supported a dominant negative impact for both variants (Donger C et al. Circulation, 1997 Nov;96:2778-81; Thomas D et al. J. Mol. Cell. Cardiol., 2010 Jan;48:230-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

-

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

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.Pro320Ser Given the weak case data and minimal controls, we consider this variant a variant of uncertain significance, probably disease causing. The variant has been seen in at least one unrelated cases of long QT syndrome (not including this patient's family), possibly two. There is weak segregation data. The variant was reported in one individual 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). Ancestry was not provided. Ackerman's group later reported a patient seen in their Mayo LQTS clinic who was a compound heterozygote for this variant and p.Pro448Leu (Giudicessi et al 2013). The patient was a female with a QTc of 499 ms, one syncopal episode, and normal hearing. Several family members who carry just p.Pro448Leu had normal QTc measurements while the proband's son carried just p.Pro320Ser and had a QTc of 505 ms. Ancestry was not provided. That case may overlap with Kapplinger et al (2009) as some of the patients had commercial genetic testing. Unfortunately insufficient information is provided in Kapplinger et al (2009) to determine if it is in fact the same case. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 1.000). The proline at codon 320 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Pro320Ala, p.Pro320His) and nearby codons (p.Val310Asn, p.Val310Ile, p.Gly314Asn, p.Gly314Arg, p.Gly314Ser, p.Gly316Glu, p.Gly316Arg, p.Gly316Val, p.Gly316Val, p.Lys318Asn, p.Thr322Ala, p.Thr322Lys, p.Thr322Met, p.Gly325Arg, p.Gly325Glu, p.Gly325Trp). In total the variant has not been seen in ~9800 published controls and individuals from publicly available population datasets. There is no variation at codon 320 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 8th, 2014). The variant is listed in dbSNP (rs199472753), however the only submission is a locus specific database noting reports with disease in the literature. The variant was not observed in the following published control samples: 1300 ostensibly healthy individuals (Kapplinger et al 2009). -

Congenital long QT syndrome Other:1

-

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:19716085). 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	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.5	D;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0050	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.95		Loss of methylation at K318 (P = 0.075);.;.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.99
gMVP		1.0
Mutation Taster		=2/98	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: rs199472753; hg19: chr11-2604701;