rs104894252

Positions:

• chr11-2570715-G-A
• chr11-2570715-G-C

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.565G>A​(p.Gly189Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G189E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 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 22 ACMG points.

• PS1: Transcript NM_000218.3 (KCNQ1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a helix (size 6) in uniprot entity KCNQ1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) 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 chr11-2570716-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 11-2570715-G-A is Pathogenic according to our data. Variant chr11-2570715-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570715-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.565G>A	p.Gly189Arg	missense_variant	3/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.565G>A	p.Gly189Arg	missense_variant	3/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.184G>A	p.Gly62Arg	missense_variant	3/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.304G>A	p.Gly102Arg	missense_variant	4/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-12720G>A		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459978 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726414

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 27, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Gly189Arg Based on the information reviewed below, we classify it as very likely disease causing. This variant has previously been reported in at least 3 unrelated individuals with LQTS. There is very strong published segregation data. Jongbloed et al. (1999) identified this variant in 2 Dutch families with LQT1. It segregated with disease in 17 affected members of one family (2 of them asymptomatic), and 3 affected members of the other (one of them asymptomatic). Wang et al. (1996) had previously reported that it segregated with disease in 3 affected siblings in a family with LQTS. Nannenberg et al. (2012) reported it in a Dutch family with LQT1 in which they traced the disease back centuries, although it is not clear if this family was included in Jongbloed et al. (According to OMIM, this variant used to be known as GLY60ARG, by Wang et al., and GLY94ARG.) Another variant at this same codon, Gly189Glu, has been reported in association with LQTS (HGMD cites Moss et al. 2007, Giudicessi et al. 2012, and another). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar glycine with a positively-charged arginine with a much bulkier side-chain. Glycine at this location is highly conserved across vertebrate species (it is an alanine in a species of falcon). Variation at nearby residues has been associated with LQTS, which may support the functional importance of this region of the protein: G179S, K183R, K183M, Y184H, Y184S, G186R, G186S, L187P, R190W, R190L, R190Q, L191P, R192C, R192H, R192P, F193L, A194P, R195W, I198V, S199A (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0. In vitro functional studies show that it results in a loss of KCNQ1 channel function (Wang et al. 1999, Barsheshet et al 2012). This residue is in the cytoplasmic S2-S3 linker. It is not entirely possible to tell from the location within the KCNQ1 protein if a variant causes disease. However, when Kapa et al. (2009) compared 388 “clinically definite” LQTS probands to ~1300 healthy controls, they found that LQTS cases were much more likely to have missense variants in the C-terminal cytoplasmic region of the KCNQ1 protein (amino acid residues 349-676), the pore region, transmembrane region, or linker region (residues 122-348)—rather than in the N-terminal domain (residues 1-121). Variants in the transmembrane-linker-pore domain of the protein were 24x more frequent in LQTS cases than in controls. In total the variant has not been seen in over 60,000 published controls and individuals from publicly available population datasets. The variant was not observed in published controls: 55 individuals (Jongbloed et al. 1999; didn’t check the other references). As of 6/5/2015, there is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. Our patient’s ancestry is Caucasian. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. This variant was not found in 1000 Genomes (http://browser.1000genomes.org/index.htm). The variant is not present in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These in -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	Identified in a patient with LQTS referred for genetic testing at GeneDx and observed in association with LQTS in the published literature (Wang et al., 1996; Wang et al., 1999; Jongbloed et al., 1999; Moss et al., 2007; Goldenberg et al., 2011; Nannenberg et al., 2012; Barsheshet et al., 2012); Published functional studies suggest damaging effect with loss of function but little dominant-negative impact (Wang et al., 1999) and reduction in normalized current (Barasheshet et al., 2012); Not observed in large population cohorts (Lek et al., 2016); 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: 22456477, 8528244, 10220144, 22373669, 27807201, 17470695, 21185501, 10376919) -

Long QT syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1999

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect KCNQ1 protein function (PMID: 10376919, 22456477). This variant has been observed to segregate with long QT syndrome in families and has been observed in individuals affected with this condition (PMID: 8528244, 22373669, 22456477, 10376919). This variant is also known as G60R in the literature. ClinVar contains an entry for this variant (Variation ID: 3114). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 189 of the KCNQ1 protein (p.Gly189Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

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:8528244;PMID:10220144;PMID:17470695;PMID:10220144). 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	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.94, 0.91
MutPred		0.89		.;Loss of methylation at R190 (P = 0.0454);.;
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
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

Other links and lift over

dbSNP: rs104894252; hg19: chr11-2591945; COSMIC: COSV50133835;