NM_000218.3:c.1781G>A

Variant names:

• chr11-2778024-G-A
• rs199472815
• NM_000218.3:c.1781G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1781G>A​(p.Arg594Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000074044: Experimental studies have shown that this missense change affects KCNQ1 function (PMID:15051636, 15935335, 20662986, 25453094).; SCV000919558: Multiple publications report in-vitro experimental evidence demonstrating impaired trafficking and activity of the protein channels in cells expressing the variant (e.g. Wilson_2005, Zhang_2014).; SCV004836482: Functional studies have shown that this variant results in decreased cell surface protein expression and loss of potassium channel function (PMID:15051636, 15140888, 20662986) by causing retention of the mutant protein in the endoplasmic reticulum and disturbing channel trafficking (PMID:15935335, 24912595).; SCV000712007: In vitro functional studies provide some evidence that this variant impacts protein function (Huang 2001, Westenskow 2004, Wilson 2005, Horr 2011, Harmer 2014, Zhang 2014); SCV000280151: Studies involving human K+ channels with the variant have a 3 times higher proportion of ER co localization compared to wild type channels (Wilson et al 2005). Howard et al analyzed the structure of the K+ channel with the variant in question and noted that mutant channels have a much lower elution volume than wild type channels.; SCV000319597: "In multiple assays testing KCNQ1 function, this variant showed functionally abnormal results (Westenskow P et al. Circulation. 2004;109(15):1834-41; Kanki H et al. J Biol Chem. 2004;279(32):33976-83; Zhang M et al. Proc Natl Acad Sci U.S.A. 2014;111(50):E5383-92)."; SCV001434953: Experimental studies have shown that this missense change results in reduction or loss of channel function (PMID 15051636,15140888, 25453094).; SCV003920106: In addition, functional studies have shown a deleterious effect of this variant through abnormal protein trafficking and loss of channel function (Huang 2001 PMID:11530100, Wentenskow 2004 PMID:15051636, Wilson 2005 PMID:15935335, Zhang 2014 PMID:25453094).; SCV004358441: Functional studies have shown that this variant results in decreased cell surface protein expression and loss of potassium channel function (PMID:15051636, 15140888, 20662986) by causing retention of the mutant protein in the endoplasmic reticulum and disturbing channel trafficking (PMID:15935335, 24912595).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R594L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 7.54
• Publications: 51 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000074044: Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 15051636, 15935335, 20662986, 25453094).; SCV000919558: Multiple publications report in-vitro experimental evidence demonstrating impaired trafficking and activity of the protein channels in cells expressing the variant (e.g. Wilson_2005, Zhang_2014).; SCV004836482: Functional studies have shown that this variant results in decreased cell surface protein expression and loss of potassium channel function (PMID: 15051636, 15140888, 20662986) by causing retention of the mutant protein in the endoplasmic reticulum and disturbing channel trafficking (PMID: 15935335, 24912595).; SCV000712007: In vitro functional studies provide some evidence that this variant impacts protein function (Huang 2001, Westenskow 2004, Wilson 2005, Horr 2011, Harmer 2014, Zhang 2014); SCV000280151: Studies involving human K+ channels with the variant have a 3 times higher proportion of ER co localization compared to wild type channels (Wilson et al 2005). Howard et al analyzed the structure of the K+ channel with the variant in question and noted that mutant channels have a much lower elution volume than wild type channels.; SCV000319597: "In multiple assays testing KCNQ1 function, this variant showed functionally abnormal results (Westenskow P et al. Circulation. 2004;109(15):1834-41; Kanki H et al. J Biol Chem. 2004;279(32):33976-83; Zhang M et al. Proc Natl Acad Sci U.S.A. 2014;111(50):E5383-92)."; SCV001434953: Experimental studies have shown that this missense change results in reduction or loss of channel function (PMID 15051636,15140888, 25453094).; SCV003920106: In addition, functional studies have shown a deleterious effect of this variant through abnormal protein trafficking and loss of channel function (Huang 2001 PMID:11530100, Wentenskow 2004 PMID:15051636, Wilson 2005 PMID:15935335, Zhang 2014 PMID:25453094).; SCV004358441: Functional studies have shown that this variant results in decreased cell surface protein expression and loss of potassium channel function (PMID: 15051636, 15140888, 20662986) by causing retention of the mutant protein in the endoplasmic reticulum and disturbing channel trafficking (PMID: 15935335, 24912595).
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000218.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2778024-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2502702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, Jervell and Lange-Nielsen syndrome 1, long QT syndrome 1, familial atrial fibrillation, short QT syndrome type 2, long QT syndrome, atrial fibrillation, familial, 3, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 11-2778024-G-A is Pathogenic according to our data. Variant chr11-2778024-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1781G>A	p.Arg594Gln	missense	Exon 15 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1685G>A	p.Arg562Gln	missense	Exon 14 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1511G>A	p.Arg504Gln	missense	Exon 16 of 17	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1781G>A	p.Arg594Gln	missense	Exon 15 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1400G>A	p.Arg467Gln	missense	Exon 15 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1778G>A	p.Arg593Gln	missense	Exon 15 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250968 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461426 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727042

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111994

Other (OTH) AF: 0.0000662 AC: 4 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000352 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
4	-	-	Long QT syndrome 1 (4)
3	-	-	Long QT syndrome (3)
1	-	-	Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 (1)
1	-	-	Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 (1)
1	-	-	Cardiac arrhythmia (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Congenital long QT syndrome (2)
1	-	-	Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
CardioboostArm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.85
Sift	Benign	0.047	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.65		Loss of MoRF binding (P = 0.0174)
MVP		0.97
MPC		1.3
ClinPred		0.85	D
GERP RS		3.1
PromoterAI		0.0052	Neutral
Varity_R		0.47
gMVP		0.94
Mutation Taster		=20/80	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199472815; hg19: chr11-2799254;