rs199473448

chr11-2445439-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):c.341T>C(p.Leu114Pro) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L114L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.03

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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 11-2445439-T-C is Pathogenic according to our data. Variant chr11-2445439-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2445439-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.341T>C	p.Leu114Pro	missense_variant	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.341T>C	p.Leu114Pro	missense_variant	1/15
KCNQ1	NM_001406838.1	c.341T>C	p.Leu114Pro	missense_variant	1/11
KCNQ1	NM_001406837.1	c.-22T>C		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.341T>C	p.Leu114Pro	missense_variant	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000345015.4	n.118T>C		non_coding_transcript_exon_variant	1/3	1
KCNQ1	ENST00000496887.7	c.80T>C	p.Leu27Pro	missense_variant	2/16	5
KCNQ1	ENST00000646564.2	c.341T>C	p.Leu114Pro	missense_variant	1/11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 25, 2022

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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 17053194, 19114714, 19841300, 25348405). 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. ClinVar contains an entry for this variant (Variation ID: 53036). This missense change has been observed in individuals with long QT syndrome (PMID: 12402336). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 114 of the KCNQ1 protein (p.Leu114Pro). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2017

The p.L114P variant (also known as c.341T>C), located in coding exon 1 of the KCNQ1 gene, results from a T to C substitution at nucleotide position 341. The leucine at codon 114 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a long QT syndrome cohort, but clinical details were limited (Jongbloed R et al. Hum. Mutat. 2002;20:382-91). Functional studies in multiple cell types indicate that this variant causes loss of function as a result of a trafficking defect (Dahimène S et al. Circ. Res. 2006;99:1076-83). Internal structural analysis suggests that this alteration is significantly disruptive in a sensitive region and more disruptive than a nearby known pathogenic variant (Long SB et al. Nature. 2007;450(7168):376-82). 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. -

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:12402336;PMID:17053194;PMID:19114714). 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	1.0
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.98
MutPred		0.85		.;Gain of catalytic residue at N112 (P = 0.0576);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.95
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: rs199473448; hg19: chr11-2466669;