chr11-2570706-G-A

Position:

• chr11-2570706-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000218.3(KCNQ1):​c.556G>A​(p.Gly186Ser) 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 Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• 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 Likely_pathogenic. Variant got 9 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, 0.991
• PP5: Variant 11-2570706-G-A is Pathogenic according to our data. Variant chr11-2570706-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67082.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=2}. Variant chr11-2570706-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.556G>A	p.Gly186Ser	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>A	p.Gly186Ser	missense_variant	3/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.175G>A	p.Gly59Ser	missense_variant	3/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.295G>A	p.Gly99Ser	missense_variant	4/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-12729G>A		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with KCNQ1-related disorder (PMID: 17470695). Different missense changes at the same codon (p.Gly186Arg, p.Gly186Asp, p.Gly186Cys, p.Gly186Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053065, VCV000200894, VCV000207967, VCV000432149). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 17, 2018	The KCNQ1 c.556G>A (p.Gly186Ser) variant is a missense variant that has been identified in a heterozygous state in ten individuals with long QT syndrome type I (Moss et al. 2007; Zareba et al. 2003). These patients were later described as displaying the Romano-Ward phenotype (Hedley et al. 2009). Control data are unavailable for this variant, and it is not reported in the 1000 Genomes Project, Exome Sequencing Project, Exome Aggregation Consortium, or Genome Aggregation Database in a region of good sequencing coverage, suggesting it is rare. The p.Gly186Ser variant is located in a well-conserved amino acid residue in a transmembrane protein domain, and other variants affecting the same and nearby residues have also been reported in association with long QT syndrome. Based on the available evidence, the p.Gly186Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for long QT syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 11, 2023

The c.556G>A (p.Gly186Ser) variant in KCNQ1 gene, that encodes for potassium voltage-gated channel subfamily Q member 1, has been identified in heterozygous status in at least ten individuals with Long QT syndrome 1 (LQTS1) (PMID: 17470695, 14678125). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.937). This variant is found to be absent in the general population database (gnomAD). Different missense changes at the same codon (p.Gly186Arg, p.Gly186Asp, p.Gly186Cys, p.Gly186Val) have been reported as pathogenic/ likely pathogenic by several ClinVar submitters (ClinVar ID: 53065, 207967, 200894, 432149). Therefore, the c.556G>A (p.Gly186Ser) variant in the KCNQ1 gene is classified as likely pathogenic. -

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:14678125;PMID:17470695;PMID:19862833). 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	0.74
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	.;L;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.97, 0.87
MutPred		0.93		.;Gain of helix (P = 0.062);.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.84
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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; COSMIC: COSV105028516;