rs120074191

Variant names:

• chr11-2445448-C-T
• rs120074191
• NM_000218.3:c.350C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000218.3(KCNQ1):​c.350C>T​(p.Pro117Leu) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 5.28

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 11-2445448-C-T is Pathogenic according to our data. Variant chr11-2445448-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3141.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-2445448-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.350C>T	p.Pro117Leu	missense_variant	Exon 1 of 16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.350C>T	p.Pro117Leu	missense_variant	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1	c.350C>T	p.Pro117Leu	missense_variant	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1	c.-13C>T		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.350C>T	p.Pro117Leu	missense_variant	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000345015.4	n.127C>T		non_coding_transcript_exon_variant	Exon 1 of 3	1
KCNQ1	ENST00000496887.7	c.89C>T	p.Pro30Leu	missense_variant	Exon 2 of 16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.350C>T	p.Pro117Leu	missense_variant	Exon 1 of 11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00211 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Oct 20, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Long QT syndrome Pathogenic:1

Apr 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Pro117 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects KCNQ1 protein function (PMID: 19114714, 17053194, 29532034). This variant has been observed in individual(s) with clinical features of long QT syndrome (PMID: 11684219, 19716085, 30079003). ClinVar contains an entry for this variant (Variation ID: 3141). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 117 of the KCNQ1 protein (p.Pro117Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:11684219;PMID:17053194;PMID:19114714;PMID:19716085). 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
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.88
MutPred		0.89		.;Loss of sheet (P = 0.0457);
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.92
gMVP		0.96

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: rs120074191; hg19: chr11-2466678;