rs199473455

Positions:

• chr11-2571332-C-G
• chr11-2571332-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_000218.3(KCNQ1):​c.612C>G​(p.Ile204Met) variant causes a missense change involving the alteration of a non-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. I204F) 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:1 U:1 O:1
• Conservation: PhyloP100: -0.339

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2571330-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 11-2571332-C-G is Pathogenic according to our data. Variant chr11-2571332-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53079.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1}. Variant chr11-2571332-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.612C>G	p.Ile204Met	missense_variant	4/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.612C>G	p.Ile204Met	missense_variant	4/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.231C>G	p.Ile77Met	missense_variant	4/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.351C>G	p.Ile117Met	missense_variant	5/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-12103C>G		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 29, 2015

This sequence change replaces isoleucine with methionine at codon 204 of the KCNQ1 protein (p.Ile204Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. In summary, this is a rare missense change which has been reported in several affected individuals and has been shown to have some effect on protein function. For these reasons, this variant has been classified as Likely Pathogenic. This variant is not present in population databases and has been reported in several long QT patients (PMID: 16414944, 19841298, 23158531). ClinVar contains an entry for this variant (Variation ID: 53079). In an experimental study, this variant was shown to affect potassium channel function (PMID: 20421371). Furthermore, another sequence change which also affects this codon (p.Ile204Phe) has been shown to reduce channel function (PMID: 20421371, 25444851). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 19, 2020

- -

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:16414944;PMID:19716085;PMID:20421371). 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	Benign	0.17
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;D;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.063	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.70	.;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Pathogenic	0.75
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.98	.;D;.
Vest4		0.91, 0.92
MutPred		0.86		.;Loss of helix (P = 0.0093);.;
MVP		0.96
MPC		1.1
ClinPred		0.91	D
GERP RS		-1.7
Varity_R		0.62
gMVP		0.92

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: rs199473455; hg19: chr11-2592562;