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rs74462309

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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. 13/21 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

Scores

17
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 8.73
Variant links:
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]

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ACMG classification

Classification made for transcript

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
KCNQ1NM_000218.3 linkuse as main transcriptc.944A>C p.Tyr315Ser missense_variant 7/16 ENST00000155840.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.944A>C p.Tyr315Ser missense_variant 7/161 NM_000218.3 P1P51787-1
KCNQ1ENST00000335475.6 linkuse as main transcriptc.563A>C p.Tyr188Ser missense_variant 7/161 P51787-2
KCNQ1ENST00000496887.7 linkuse as main transcriptc.683A>C p.Tyr228Ser missense_variant 8/165
KCNQ1ENST00000646564.2 linkuse as main transcriptc.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:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 27, 2022Not 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 submitterclinical testingInvitaeMar 09, 2020For 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 submitterclinical testingAmbry GeneticsDec 16, 2020The 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 providedliterature onlyCardiovascular 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs74462309; hg19: chr11-2604687; API