chr11-2572015-G-A

Position:

• chr11-2572015-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000218.3(KCNQ1):​c.686G>A​(p.Gly229Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 9.30

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 12) in uniprot entity KCNQ1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 11-2572015-G-A is Pathogenic according to our data. Variant chr11-2572015-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53085.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Pathogenic=2}. Variant chr11-2572015-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.686G>A	p.Gly229Asp	missense_variant, splice_region_variant	5/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.686G>A	p.Gly229Asp	missense_variant, splice_region_variant	5/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.305G>A	p.Gly102Asp	missense_variant, splice_region_variant	5/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.425G>A	p.Gly142Asp	missense_variant, splice_region_variant	6/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-11420G>A		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459792 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Atrial fibrillation, familial, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2014

- -

KCNQ1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported in multiple unrelated individuals with features of KCNQ1-related disorders including early-onset atrial fibrillation, borderline QT prolongation, and sudden cardiac death (PMID: 24096004, 30967788, 34076677). Functional analyses including patch-clamp studies support a gain-of-function, arrhythmogenic effect for the c.686G>A (p.Gly229Asp) variant (PMID: 24096004, 30967788). This variant is absent from the gnomAD population database and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, c.686G>A (p.Gly229Asp) is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 12, 2012

p.Gly229Asp (GGC>GAC): c.686 G>A in exon 5 of the KCNQ1 gene (NM_000218.2). The Gly229Asp variant in the KCNQ1 gene has been reported in one individual with arrythmia and it was absent from 190 Caucasian control individuals (Ueda K et al., 2009). Additionally, the NHLBI ESP Exome Variant Server reports Gly229Asp was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Mutations in nearby residues (Ser225Leu, Ala226Val, Arg231Cys, Arg231His) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. In summary, Gly229Asp in the KCNQ1 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 26, 2020

This variant has been reported to affect KCNQ1 protein function (PMID: 30967788, 24096004). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been observed in individual(s) with atrial fibrillation and/or long QT syndrome (PMID: 30967788, 24096004, 19165230). ClinVar contains an entry for this variant (Variation ID: 53085). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 229 of the KCNQ1 protein (p.Gly229Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

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:19165230). 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	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0060	D;D;T
Polyphen		1.0	.;D;D
Vest4		0.99, 0.99
MutPred		0.88		.;Gain of helix (P = 0.0078);.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.95
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: rs199472708; hg19: chr11-2593245;