11-2572970-C-A

Position:

• chr11-2572970-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.905C>A​(p.Ala302Glu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A302T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.68

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 18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr11-2572970-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 11-2572970-C-A is Pathogenic according to our data. Variant chr11-2572970-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572970-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.905C>A	p.Ala302Glu	missense_variant	6/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.905C>A	p.Ala302Glu	missense_variant	6/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.524C>A	p.Ala175Glu	missense_variant	6/16	1
KCNQ1	ENST00000496887.7	c.644C>A	p.Ala215Glu	missense_variant	7/16	5
KCNQ1	ENST00000646564.2	c.478-10465C>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces alanine with glutamic acid at codon 302 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved pore-forming region (a.a. 300-320). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four unrelated individuals affected with long QT syndrome (PMID: 26318259, 26669661, ClinVar: SCV000817627.3, SCV000234432.9), and in an individual suspected of having long QT syndrome (PMID: 19716085). It has been shown that this variant segregates with disease in two of the families (PMID: 26669661, ClinVar SCV000234432.9). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Ala302Val, is known to be disease-causing (ClinVar variation ID: 36439), indicating that alanine at this position is important for KCNQ1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 23, 2023	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 302 of the KCNQ1 protein (p.Ala302Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 19716085; Invitae). ClinVar contains an entry for this variant (Variation ID: 67121). 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. This variant disrupts the p.Ala302 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17905336, 19808498, 25786344, 27917693). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2013

p.Ala302Glu (GCG>GAG): c.905 C>A in exon 6 of the KCNQ1 gene (NM_000218.2). The Ala302Glu mutation in the KCNQ1 gene has been reported in one individual with LQTS and absent from 2,600 control alleles (Kapplinger J et al., 2009). Ala302Glu results in a non-conservative amino acid substitution of a non-polar Alanine with a negatively charged Glutamic acid at a position that is conserved across species. Other mutations at this residue (Ala302Thr, Ala302Val) and nearby residues (Ala300Thr, Leu303Pro) have been reported in association with LQTS, further supporting the functional importance of this codon and this region of the protein. Furthermore, Ala302Glu 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. The variant is found in LQT panel(s). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2019

The p.A302E variant (also known as c.905C>A), located in coding exon 6 of the KCNQ1 gene, results from a C to A substitution at nucleotide position 905. The alanine at codon 302 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant was identified in one individual undergoing genetic testing for long QT syndrome (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Another variant, p.A302, has been described in the same codon in trans with a second KCNQ1 alteration in an individual with Jervell and Lange-Nielsen syndrome and alone in individuals with long QT syndrome (Wang C et al. Acta Otolaryngol., 2017 May;137:522-528; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Chung SK et al. Heart Rhythm, 2007 Oct;4:1306-14; Olesen MS et al. Heart Rhythm, 2014 Feb;11:246-51). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Congenital long QT syndrome 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: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
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.97		Gain of phosphorylation at Y299 (P = 0.1645);.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.99
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922365; hg19: chr11-2594200;