rs74462309

chr11-2583457-A-Cchr11-2583457-A-Gchr11-2583457-A-T

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.944A>C(p.Tyr315Ser) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y315C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 8.73

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, 15 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 chr11-2583457-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-2583457-A-C is Pathogenic according to our data. Variant chr11-2583457-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 53139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583457-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.944A>C	p.Tyr315Ser	missense_variant	7/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.944A>C	p.Tyr315Ser	missense_variant	7/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.563A>C	p.Tyr188Ser	missense_variant	7/16	1
KCNQ1	ENST00000496887.7	c.683A>C	p.Tyr228Ser	missense_variant	8/16	5
KCNQ1	ENST00000646564.2	c.500A>C	p.Tyr167Ser	missense_variant	3/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a dominant negative effect (Chouabe et al., 1997; Mohammad-Panah et al., 1999; Ren et al., 2010); Transgenic rabbit studies demonstrate that rabbits heterozygous for the Y315S variant had an LQTS phenotype due to the elimination of the rapidly activating component (IKr) and the slowly activating component (IKs) channel currents in cardiomyocytes (Brunner et al., 2008; Castiglione et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10090886, 9312006, 17470695, 34505893, 35138621, 34313298, 34601592, 35300995, 27210304, 20833965, 9386136, 27210307, 12566525, 10220144, 18464931, 28438721) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 09, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr315 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24217263, 12702160, 18774102, 21451124, 11087258, 21451124). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect KCNQ1 protein function (PMID: 9312006, 20833965, 18464931, 10090886, 12522251). This variant has been observed in individual(s) with long QT syndrome (PMID: 24217263, 19490272, 10220144, 9386136). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 53139). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with serine at codon 315 of the KCNQ1 protein (p.Tyr315Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2020

The p.Y315S pathogenic mutation (also known as c.944A>C), located in coding exon 7 of the KCNQ1 gene, results from an A to C substitution at nucleotide position 944. The tyrosine at codon 315 is replaced by serine, an amino acid with dissimilar properties. This alteration impacts the highly conserved ion selectivity filter (TIGYGD) located between transmembrane helices S5 and S6. This alteration has been reported in unrelated individuals reported to have long QT syndrome (LQTS), has been reported as occurring de novo in at least one case, and has been reported in affected individuals within families (Donger C et al. Circulation. 1997;96(9):2778-81; Jongbloed RJ et al. Hum Mutat. 1999;13(4):301-10; Moss AJ et al. Circulation. 2007;115(19):2481-9). In addition, this alteration has been reported to result in LQTS phenotype in a transgenic rabbit model due to elimination of IKs current, and in vitro studies report abnormal channel function as a result of this alteration (Chouabe C et al. EMBO J. 1997;16(17):5472-9; Brunner et al. J Clin Invest. 2008; 18(6):2246-59). Internal structural analysis indicates that this variant disrupts the ion channel pore and is expected to eliminate the K+ selectivity of the K+ channel (Tao X et al. Science. 2009;326(5960):1668-74; Whorton MR and MacKinnon R. Cell. 2011;147(1):199-208; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:9386136;PMID:10220144;PMID:12566525;PMID:18464931;PMID:20833965;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	0.99
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.4	D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.93		Gain of glycosylation at Y315 (P = 0.0044);.;.;
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.98
gMVP		0.99

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: rs74462309; hg19: chr11-2604687;