chr11-2570707-G-A

Position:

• chr11-2570707-G-A

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.557G>A​(p.Gly186Asp) 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. 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. G186R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.59

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr11-2570706-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-2570707-G-A is Pathogenic according to our data. Variant chr11-2570707-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.557G>A	p.Gly186Asp	missense_variant	3/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.557G>A	p.Gly186Asp	missense_variant	3/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.176G>A	p.Gly59Asp	missense_variant	3/16	1
KCNQ1	ENST00000496887.7	c.296G>A	p.Gly99Asp	missense_variant	4/16	5
KCNQ1	ENST00000646564.2	c.478-12728G>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Jan 01, 2013

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 10, 2020

- -

Congenital long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2018

The p.Gly186Asp variant in KCNQ1 has been reported in the heterozygous state in 2 individuals with long QT syndrome (LQTS) and in the homozygous state in 1 indi vidual with Jervell and Lange-Nielsen syndrome (Vyas 2016a, Vyas 2016b, Itoh 201 6). Additionally, the variant segregated with prolonged QT interval in 5 individ uals from 2 families (Vyas 2016a, Vyas 2016b), and was absent from large populat ion studies. Computational prediction tools and conservation analysis suggest th at the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Finally, several variants at the same positi on have been reported in individuals with LQTS (ClinVar variation IDs: 432149, 2 00894, 53065, 67082); however, their clinical significance is unknown due to lim ited available data. In summary, although additional studies are required to ful ly establish its clinical significance, the p.Gly186Asp variant is likely pathog enic. ACMG/AMP Criteria applied: PM2, PP1_Moderate, PP3, PS4_Supporting. -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2018

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. The observation of one or more missense substitutions at this codon (p.Gly186Asp and p.Gly186Arg) in affected individuals suggests that this may be a clinically significant residue (PMID: 27485560, 27041150, 22949429). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with long QT syndrome in families (PMID: 27485560) and has been reported in an individual affected with this disease (PMID: 26669661). This variant has been observed in a homozygous individual affected with Jervell and Lange-Nielsen syndrome (PMID: 27041150). ClinVar contains an entry for this variant (Variation ID: 207967). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 186 of the KCNQ1 protein (p.Gly186Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 08, 2020

This missense variant replaces glycine with aspartic acid at codon 186 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with long QT syndrome in the heterozygous state and in an individual with Jervell and Lange-Nielsen syndrome in the homozygous state (PMID: 26669661, 27041150). This variant has been shown to segregate with long QT syndrome in two families (PMID: 27041150, 27485560). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.046	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.92, 0.74
MutPred		0.87		.;Loss of catalytic residue at G186 (P = 0.0219);.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.89
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: rs794728568; hg19: chr11-2591937;