11-2570730-G-C

Variant names:

• chr11-2570730-G-C
• rs199472699
• NM_000218.3:c.580G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000218.3(KCNQ1):​c.580G>C​(p.Ala194Pro) variant causes a missense change. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A194V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3 O:1
• Conservation: PhyloP100: 5.17
• Publications: 6 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 28 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.580G>C	p.Ala194Pro	missense_variant	Exon 3 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.580G>C	p.Ala194Pro	missense_variant	Exon 3 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Oct 13, 2014

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.Ala194Pro This variant has been reported in two unrelated individuals with long QT syndrome. Splawski et al (2000) identified the variant in one individual with long QT syndrome. Kotta et al (2010) genotyped families of Greek descent with long QT syndrome and identified the variant in one infant with a QTc of 480 ms. While the two publications both include European long QT samples, Kotta et al (2010) specifically state that there is no published data on the Greek long QT population therefore it is likely that these are two separate and unrelated probands with long QT and this variant. Neither publication included segregation data. This is a conservative amino acid change with a nonpolar Alanine replaced with a nonpolar Proline at codon 194. The Alanine at codon 194 is completely conserved as are neighboring residues. In silico analysis with PolyPhen2 predicts the variant to be probably damaging. Variants in nearby codons have been associated with long QT syndrome (p.Arg192Pro, p.Arg195Trp, p.Ile198Val) (http://www.fsm.it/cardmoc/, Kapplinger et al 2009, Napolitano 2005). The variant is in the intracellular linker between the S2 and S3 transmembrane domains (Kapplinger et al 2009). This region of the channel is particularly enriched with pathogenic variants. Variants in this region and elsewhere in the transmembrane domains have been reported as an independent risk factor for clinical severity (Moss et al 2007). We were unable to find in vitro data on the functional impact of the variant. Pan et al (2009) note in the introduction to their manuscript that this variant has been shown to reduce IK currents, however they do not provide the primary reference. Kotta et al (2010) did not observe the variant in 100 control individuals of Greek descent. Splawski et al (2000) did not find variant in 200 control individuals. Thus in total this variant has not been seen in 300 published controls. Based on these data it seems likely, though not definite, that this variant causes long QT syndrome. -

Apr 05, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The KCNQ1 c.580G>C variant affects a conserved nucleotide, resulting in amino acid change from Ala to Pro. 4/4 in-silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant has been reported in at least 3 patients with LQTS and was not found in 120200 control chromosomes. In addition, one clinical laboratory classified this variant as pathogenic without evidence to independently evaluate. Taken together, this variant was classified as VUS-possibly pathogenic. -

Long QT syndrome Uncertain:1

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 194 of the KCNQ1 protein (p.Ala194Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 10973849, 21063070). ClinVar contains an entry for this variant (Variation ID: 53075). 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%. 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. -

Cardiovascular phenotype Uncertain:1

Aug 10, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.580G>C (p.A194P) alteration is located in exon 3 (coding exon 3) of the KCNQ1 gene. This alteration results from a G to C substitution at nucleotide position 580, causing the alanine (A) at amino acid position 194 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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:10973849). 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	0.99
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;M;.
PhyloP100		5.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98, 0.97
MutPred		0.93		.;Loss of MoRF binding (P = 0.0404);.;
MVP		0.99
MPC		1.3
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.99
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs199472699; hg19: chr11-2591960;