11-2847803-G-T

Variant names:

• chr11-2847803-G-T
• rs147445322
• NM_000218.3:c.1831G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PP2 PP3_Moderate PP5

The NM_000218.3(KCNQ1):​c.1831G>T​(p.Asp611Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000846 in 1,419,094 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV003439597: Experimental studies have shown that this missense change does not substantially affect KCNQ1 function (PMID:15500450, 21451124).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D611N) has been classified as Uncertain significance. The gene KCNQ1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 4.89
• Publications: 17 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-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003439597: Experimental studies have shown that this missense change does not substantially affect KCNQ1 function (PMID: 15500450, 21451124).
• 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, 0.907
• PP5: Variant 11-2847803-G-T is Pathogenic according to our data. Variant chr11-2847803-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67060.

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.1831G>T	p.Asp611Tyr	missense	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1735G>T	p.Asp579Tyr	missense	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1561G>T	p.Asp521Tyr	missense	Exon 17 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.1831G>T	p.Asp611Tyr	missense	Exon 16 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1450G>T	p.Asp484Tyr	missense	Exon 16 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1828G>T	p.Asp610Tyr	missense	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000552 AC: 1 AN: 181208 AF XY: 0.0000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000846 AC: 12 AN: 1419094 Hom.: 0 Cov.: 31 AF XY: 0.00000855 AC XY: 6 AN XY: 702052

African (AFR) AF: 0.00 AC: 0 AN: 32596

American (AMR) AF: 0.00 AC: 0 AN: 39010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.000321 AC: 12 AN: 37424

South Asian (SAS) AF: 0.00 AC: 0 AN: 80826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089980

Other (OTH) AF: 0.00 AC: 0 AN: 58732

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000280 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Long QT syndrome (2)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
CardioboostArm	Benign	0.027
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.31	N
REVEL	Pathogenic	0.69
Sift	Benign	0.081	T
Sift4G	Uncertain	0.040	D
Polyphen		0.18	B
Vest4		0.88
MutPred		0.79		Loss of disorder (P = 0.0332)
MVP		0.95
MPC		0.53
ClinPred		0.49	T
GERP RS		2.9
Varity_R		0.71
gMVP		0.91
Mutation Taster		=23/77	disease causing

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: rs147445322; hg19: chr11-2869033;