rs147445322

Positions:

• chr11-2847803-G-A
• chr11-2847803-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM5 BP4

The NM_000218.3(KCNQ1):​c.1831G>A​(p.Asp611Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000757 in 1,571,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D611Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:1 O:1
• Conservation: PhyloP100: 4.89

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]

KCNQ1-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a region_of_interest Interaction with AKAP9 (size 28) in uniprot entity KCNQ1_HUMAN there are 38 pathogenic changes around while only 1 benign (97%) in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2847803-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67060.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38976586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1831G>A	p.Asp611Asn	missense_variant	16/16	ENST00000155840.12
KCNQ1-AS1	NR_130721.1	n.778-7361C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1831G>A	p.Asp611Asn	missense_variant	16/16	1	NM_000218.3	P1
KCNQ1-AS1	ENST00000440887.2	n.777-7361C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000717 AC: 13 AN: 181208 Hom.: 0 AF XY: 0.0000617 AC XY: 6 AN XY: 97278

Gnomad AFR exome AF: 0.0000917

Gnomad AMR exome AF: 0.000108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad SAS exome AF: 0.0000820

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000812

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000761 AC: 108 AN: 1419094 Hom.: 0 Cov.: 31 AF XY: 0.0000755 AC XY: 53 AN XY: 702052

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.000154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000534

Gnomad4 SAS exome AF: 0.0000866

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000807

Gnomad4 OTH exome AF: 0.0000681

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74450

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000641 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000117 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PM2, PM5 -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces aspartic acid with asparagine at codon 611 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 22727609, 33614747), in an individual referred for long QT syndrome test (PMID: 19716085), and in an individual suspected of having Jervell and Lange-Nielsen Syndrome (27917693). It has also been reported in an individual among exome sequencing participants not selected for cardiovascular disorders (PMID: 23861362) and in another two individuals with normal QTc internal (PMID: 26159999, 27917693). This variant has been identified in 17/212554 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 611 of the KCNQ1 protein (p.Asp611Asn). This variant is present in population databases (rs147445322, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Jervell and Lang-Nielsen syndrome and/or clinical features of long QT syndrome (PMID: 19716085, 22727609, 25554238, 27917693, 30530868). ClinVar contains an entry for this variant (Variation ID: 67059). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. 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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 10, 2018	The p.Asp611Asn variant in KCNQ1 has been reported in 3 individuals with Long QT syndrome (Andrsova 2012, Hedley 2009, Kapplinger 2009). It was also identified in 1 child with congenital profound hearing loss and a borderline QTc of 446 ms ec who had a second VUS in KCNQ1 in trans. The variant was found in the heterozy gous state in the child's unaffected mother (Wang 2017). In another study this variant was found in a heterozygous individual whose mean QTc interval was not s tatistically different than the mean QTc interval observed in 6061 Danish contro l individuals that were negative for the variant (Ghouse 2015). This variant ha s been identified in several populations by the Genome Aggregation Database with the highest allele frequency of 10/86082 European chromosomes (gnomAD, http://g nomad.broadinstitute.org/; dbSNP rs147445322) and is reported in ClinVar (Variat ion ID: 67059) by several laboratories or studies. Although the variant has been seen in unaffected individuals and in the general population, we cannot rule ou t a causative role due to reduced penetrance and variable expressivity that has been noted in some long QT families. Computational prediction tools and conserva tion analysis do not provide strong support for or against an impact to the prot ein. In summary, due its presence in both affected and unaffected individuals, l imited familial segregation data, and its frequency in the general population, t he clinical significance of the p.Asp611Asn variant is uncertain. ACMG/AMP Crite ria applied: None. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	Variant summary: KCNQ1 c.1831G>A (p.Asp611Asn) results in a conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal (IPR013821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 181208 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in KCNQ1 causing Long QT Syndrome (7.2e-05 vs 0.0001), allowing no conclusion about variant significance. c.1831G>A has been reported in the literature in individuals affected with Long QT Syndrome or related phenotypes (Kapplinger_2009, Thauvin-Robinet_2019, Andrsova_2012, Tse_2021, Kwok_2018, Illikova_2015), although one publication found no significant difference in electrocardiogram results between a carrier and non-carriers of the variant (Ghouse_2015). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 26159999, 27917693, 31019283, 22727609, 33614747, 30530868, 25554238). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2022	Reported multiple times in association with LQTS or sudden cardiac arrest, though many publications lack patient-specific data (Kapplinger et al., 2009; Andrsova et al., 2012; Illikova et al., 2015; Coto et al., 2017; Kwok et al., 2018; Giudicessi et al, 2018); Reported in a Danish cohort screened for LQTS variants where QTc intervals in carriers were not statistically different compared with non-carriers (Ghouse et al., 2015); Reported in a 6-year-old Chinese proband with congential profound deafness and QTc of 446. He also harbored a second missense variant in trans in the KCNQ1 gene. The p.(D611N) variant was inherited from his mother with normal hearing and a normal QTc interval (Wang et al., 2017).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 22727609, 23861362, 28749187, 22378279, 19862833, 25554238, 26159999, 29197658, 26633542, 25854863, 30530868, 29884292, 31019283, 32048431, 33614747, 27917693, 19716085) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 20, 2023	- -

Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 21, 2018

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2022

The c.1831G>A (p.D611N) alteration is located in exon 16 (coding exon 16) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 1831, causing the aspartic acid (D) at amino acid position 611 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 01, 2023

This missense variant replaces aspartic acid with asparagine at codon 611 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 22727609, 33614747), in an individual suspected to be affected with long QT syndrome (PMID: 19716085), and in an individual suspected of having Jervell and Lange-Nielsen Syndrome (27917693). It has also been reported in individuals without diagnoses of KCNQ1-related disorders (PMID: 23861362, 26159999, 27917693). This variant has been identified in 17/212554 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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:19716085;PMID:19862833;PMID:22378279). 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	Benign	0.093
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Benign	-0.0074
Eigen_PC	Benign	0.0049
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.99	L;.;.
MutationTaster	Benign	0.61	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.53	N;N;.
REVEL	Uncertain	0.59
Sift	Benign	0.19	T;T;.
Sift4G	Benign	0.23	T;T;.
Polyphen		0.94	P;.;.
Vest4		0.76
MVP		0.95
MPC		0.38
ClinPred		0.034	T
GERP RS		2.9
Varity_R		0.52
gMVP		0.82

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: rs147445322; hg19: chr11-2869033;