11-2570706-G-T

Position:

• chr11-2570706-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.556G>T​(p.Gly186Cys) 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 Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.42

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 16 ACMG points.

• 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-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 11-2570706-G-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.556G>T	p.Gly186Cys	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.556G>T	p.Gly186Cys	missense_variant	3/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.175G>T	p.Gly59Cys	missense_variant	3/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.295G>T	p.Gly99Cys	missense_variant	4/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-12729G>T		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 02, 2016

The G186C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G186C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G186C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a likely pathogenic variant affecting the same residue (G186S) and likely pathogenic and pathogenic variants in nearby residues (Y184H, Y184S, Y184C, Y184D, G189R, R190Q, R190W) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014).Therefore, this variant is likely pathogenic -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2016

The p.G186C variant (also known as c.556G>T), located in coding exon 3 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 556. The glycine at codon 186 is replaced by cysteine, an amino acid with highly dissimilar properties. In vitro functional analysis suggests this alteration results in a significant reduction in channel current (Vanoye C et al. 2017. https://www.biorxiv.org/content/early/2017/11/21/223206). Alterations at the same amino acid position, p.G186S and p.G186R, have been reported in patients with long QT syndrome (Zareba W et al. J Cardiovasc Electrophysiol. 2003;14(11):1149-53; Kapa S et al. Circulation. 2009;120(18):1752-60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	.;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.4	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.94, 0.88
MutPred		0.84		.;Gain of sheet (P = 0.0477);.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.90
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199473398; hg19: chr11-2591936;