rs199472748

Positions:

• chr11-2583454-G-A
• chr11-2583454-G-C

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.941G>A​(p.Gly314Asp) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G314A) 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:3 O:1
• Conservation: PhyloP100: 9.36

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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr11-2583453-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 11-2583454-G-A is Pathogenic according to our data. Variant chr11-2583454-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583454-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.941G>A	p.Gly314Asp	missense_variant	7/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.941G>A	p.Gly314Asp	missense_variant	7/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.560G>A	p.Gly187Asp	missense_variant	7/16	1
KCNQ1	ENST00000496887.7	c.680G>A	p.Gly227Asp	missense_variant	8/16	5
KCNQ1	ENST00000646564.2	c.497G>A	p.Gly166Asp	missense_variant	3/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely 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

Oct 03, 2023

Not observed at significant frequency in large population cohorts (gnomAD); 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: 15466642, 23995044, 22949429, 15840476, 23124029, 29654130, 32168391, 32421437) -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 07, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 314 of the KCNQ1 protein (p.Gly314Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 22949429, 32168391). ClinVar contains an entry for this variant (Variation ID: 53138). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Gly314 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8872472, 9799083, 16922724, 22727609, 22949429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2019

The p.G314D pathogenic mutation (also known as c.941G>A), located in coding exon 7 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 941. The glycine at codon 314 is replaced by aspartic acid, an amino acid with similar properties, and is located in the ion selectivity filter (GYGD) motif of the intramembrane pore-forming region between transmembrane helices S5 and S6. This alteration has been reported in patients with long QT syndrome (LQTS), including a proband identified in utero with fetal bradycardia and 2nd degree AV block (Choi G et al. Circulation. 2004;110:2119-24; Mitchell JL et al. Circulation. 2012;126:2688-95). Several alterations impacting this amino acid have been identified in multiple patients with LQTS; and one (p.G314S, c.940G>A) has been reported to co-segregate with disease in multiple families and has demonstrated significantly reduced IKs current density in heterologous expression studies (Russell MW et al. Hum. Mol. Genet. 1996;5:1319-24; Chouabe C et al. EMBO J. 1997;16:5472-9). 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:12566525;PMID:15466642;PMID:15840476;PMID:19841300). 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	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.1	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.7	D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.98		Loss of methylation at K318 (P = 0.0822);.;.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.97
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: rs199472748; hg19: chr11-2604684;