rs199472751

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000155840.12(KCNQ1):​c.949G>A​(p.Asp317Asn) 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. 12/21 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. D317Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNQ1
ENST00000155840.12 missense

Scores

15
3
1

Clinical Significance

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

Conservation

PhyloP100: 9.36
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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in ENST00000155840.12
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-2583463-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 11-2583462-G-A is Pathogenic according to our data. Variant chr11-2583462-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583462-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.949G>A p.Asp317Asn missense_variant 7/16 ENST00000155840.12 NP_000209.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.949G>A p.Asp317Asn missense_variant 7/161 NM_000218.3 ENSP00000155840 P1P51787-1
KCNQ1ENST00000335475.6 linkuse as main transcriptc.568G>A p.Asp190Asn missense_variant 7/161 ENSP00000334497 P51787-2
KCNQ1ENST00000496887.7 linkuse as main transcriptc.688G>A p.Asp230Asn missense_variant 8/165 ENSP00000434560
KCNQ1ENST00000646564.2 linkuse as main transcriptc.505G>A p.Asp169Asn missense_variant 3/11 ENSP00000495806

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 testingGeneDxApr 23, 2018This missense change is denoted Asp317Asn (aka D317N) at the protein level and c.949 G>A at the cDNA level. The Asp317Asn mutation (also reported as Asp222Asn and Asp188Asn due to alternative nomenclature) in KCNQ1 has been reported previously in multiple individuals with LQTS, and has been shown to co-segregate with an LQTS phenotype in at least two large families (Wollnick B et al.,1997, Saarinen K et al., 1998, Chen S et al., 2003 ). Swan et al. (1999) reported the QT prolongation is exacerbated during exercise and recovery in individuals harboring the Asp317Asn mutation, consistent with the development of symptoms during exercise for several of the patients reported (Saarinen K et al., 1998, Chen S et al., 2003, Swan H et al., 1999). Considering all publications, the Asp317Asn mutation was absent from 550 control alleles (Wollnick B et al.,1997, Saarinen K et al., 1998, Swan H et al., 1999). The Asp317Asn mutation was not identified in 400 Caucasian and African American control chromosomes tested at GeneDx, and the NHLBI ESP Exome Variant Server reports Asp317Asn was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The Asp317Asn mutation affects the pore region of the cardiac potassium voltage-gated channel, KQT-like type 1, an important functional region of the protein (Wollnick B et al.,1997). Furthermore, mutations at the same codon (Asp317Gly, Asp317Tyr) as well as in neighboring codons (Gly316Arg, Gly316Glu, Gly316Val, Lys318Asn) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein. The variant is found in LQT panel(s). -
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 07, 2023This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 317 of the KCNQ1 protein (p.Asp317Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9302275, 9482580, 10973849, 11410559, 12702160, 23631430, 26063740). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp222Asn, p.Asp188Asn. ClinVar contains an entry for this variant (Variation ID: 53145). 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%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9302275, 25705178). For these reasons, this variant has been classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 27, 2017Variant summary: The KCNQ1 c.949G>A (p.Asp317Asn) variant involves the alteration of a conserved nucleotide located in the Ion transport domain (InterPro), and in the H5 loop, which is an important part of the pore (Wollnik_1997). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121152 control chromosomes. The variant has been reported in the literature to perfectly segregate with LQTS in at least two families (Wollnik_1997, Chen_2003), and was reported in a patient group which displayed the longest QT intervals as well as the most impaired heart rate responses to exercise compared to patient groups with other types of mutations in KCNQ1 (Swan_1999). Functional studies show the variant to abolish channel activity and reduce the activity of wild-type KvLQT1 by a dominant negative mechanism (Wollnik_1997). In addition, at-least one clinical diagnostic laboratory in ClinVar database has classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
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:9302275;PMID:9482580;PMID:12702160). 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
0.93
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.99
D;.;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.4
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-4.7
D;.;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;.;D
Sift4G
Uncertain
0.0050
D;.;D
Polyphen
1.0
D;.;D
Vest4
0.99
MutPred
0.94
Gain of sheet (P = 0.0477);.;.;
MVP
0.98
MPC
1.2
ClinPred
1.0
D
GERP RS
3.9
Varity_R
0.93
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: rs199472751; hg19: chr11-2604692; API