rs199472681

chr11-2445463-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000218.3(KCNQ1):c.365G>A(p.Cys122Tyr) variant causes a missense change. 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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 6.93

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 11-2445463-G-A is Pathogenic according to our data. Variant chr11-2445463-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53039.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=1, Uncertain_significance=1}. Variant chr11-2445463-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.365G>A	p.Cys122Tyr	missense_variant	1/16	ENST00000155840.12
KCNQ1	NM_001406837.1	c.3G>A	p.Met1?	start_lost	1/17
KCNQ1	NM_001406836.1	c.365G>A	p.Cys122Tyr	missense_variant	1/15
KCNQ1	NM_001406838.1	c.365G>A	p.Cys122Tyr	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.365G>A	p.Cys122Tyr	missense_variant	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000345015.4	n.142G>A		non_coding_transcript_exon_variant	1/3	1
KCNQ1	ENST00000496887.7	c.104G>A	p.Cys35Tyr	missense_variant	2/16	5
KCNQ1	ENST00000646564.2	c.365G>A	p.Cys122Tyr	missense_variant	1/11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 26, 2013

p.Cys122Tyr (TGC>TAC): c.365 G>A in exon 1 of the KCNQ1 gene (NM_000218.2). The Cys122Tyr mutation in the KCNQ1 gene has been reported in association with LQTS and Jervell and Lange-Nielson syndrome (JLNS) (Tester D et al., 2005; Giudicessi et al., 2012; Giudicessi et al., 2013). Tester et al. and Giudicessi et al. (2012) each reported Cys122Tyr in an individual with LQTS and it was absent from more than 1,500 control alleles. Giudicessi et al. (2013) identified Cys122Tyr in a patient, who harbored another mutation in the KCNQ1 gene, with a history of deafness and LQTS. Cys122Tyr was inherited from an asymptomatic mother. Cys122Tyr results in a conservative amino acid substitution of one neutral, polar amino acid with another at a position that is conserved across species. Furthermore, the Cys122Tyr mutation was not observed inapproximately 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. In summary, Cys122Tyr in the KCNQ1 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 25, 2019

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. This variant has been reported to affect KCNQ1 protein function (PMID: 29532034). This variant has been observed with a second variant in KCNQ1 in an individual affected with Jervell and Lange-Nielsen syndrome (PMID: 23392653). ClinVar contains an entry for this variant (Variation ID: 53039). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 122 of the KCNQ1 protein (p.Cys122Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

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:15840476;PMID:19841300). 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	0.99
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.4	D;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.99	.;D;.
Vest4		0.96
MutPred		0.92		.;Loss of methylation at K121 (P = 0.027);.;
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.96
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: rs199472681; hg19: chr11-2466693;