rs199473465

Positions:

• chr11-2572943-G-A
• chr11-2572943-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5 BP4

The NM_000218.3(KCNQ1):​c.878G>A​(p.Arg293His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. R293C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: -0.0700

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 Uncertain_significance. Variant got 1 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2572942-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2719402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.878G>A	p.Arg293His	missense_variant	6/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.878G>A	p.Arg293His	missense_variant	6/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.497G>A	p.Arg166His	missense_variant	6/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.617G>A	p.Arg206His	missense_variant	7/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-10492G>A		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250276 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135622

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461470 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 06, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 293 of the KCNQ1 protein (p.Arg293His). This variant is present in population databases (rs199473465, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 67118). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces arginine with histidine at codon 293 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 reported for this variant. This variant has been reported in an unaffected control individual in a long QT syndrome case-control study (PMID:19841300). This variant has been identified in 4/250276 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. -

Long QT syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Apr 15, 2020

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

The c.878G>A (p.R293H) alteration is located in exon 6 (coding exon 6) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 878, causing the arginine (R) at amino acid position 293 to be replaced by a histidine (H). 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 arginine with histidine at codon 293 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 reported for this variant. This variant has been reported in an unaffected control individual in a long QT syndrome case-control study (PMID:19841300). This variant has been identified in 4/250276 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2011

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported in the following publications (PMID:19841300). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.68	T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.66	N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.83	P;P
Vest4		0.30
MutPred		0.48		Gain of disorder (P = 0.1129);.;
MVP		0.80
MPC		0.47
ClinPred		0.091	T
GERP RS		-3.1
Varity_R		0.19
gMVP		0.83

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: rs199473465; hg19: chr11-2594173; COSMIC: COSV50105016; COSMIC: COSV50105016;