11-2572984-G-C

Variant names:

• chr11-2572984-G-C
• rs120074195
• NM_000218.3:c.919G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000218.3(KCNQ1):​c.919G>C​(p.Val307Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V307M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense, splice_region
• Scores: Splicing: ADA: 0.4976
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 6.33
• Publications: 42 publications found

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]

KCNQ1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 30 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.919G>C	p.Val307Leu	missense splice_region	Exon 6 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.919G>C	p.Val307Leu	missense splice_region	Exon 6 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.649G>C	p.Val217Leu	missense splice_region	Exon 7 of 17	NP_001393766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.919G>C	p.Val307Leu	missense splice_region	Exon 6 of 16	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.538G>C	p.Val180Leu	missense splice_region	Exon 6 of 16	ENSP00000334497.5
	KCNQ1	ENST00000496887.7	TSL:5	c.658G>C	p.Val220Leu	missense splice_region	Exon 7 of 16	ENSP00000434560.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, single submitter

Submissions by phenotype

Short QT syndrome type 2 Pathogenic:1

May 25, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Long QT syndrome Uncertain:1

Sep 05, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Short 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 Short QT syndrome in the following publications (PMID:15159330;PMID:20436212;PMID:15051636;PMID:11278406). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostArm	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	L
PhyloP100		6.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.86
Sift	Benign	0.46	T
Sift4G	Benign	0.20	T
Polyphen		0.80	P
Vest4		0.95
MutPred		0.81		Loss of catalytic residue at V307 (P = 0.0505)
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.83
gMVP		0.98
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.50
dbscSNV1_RF	Benign	0.55
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

Other links and lift over

dbSNP: rs120074195; hg19: chr11-2594214;