rs794728559

Variant names:

• chr11-2583540-C-CCAG
• rs794728559
• NM_000218.3:c.1029_1031dupAGC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000218.3(KCNQ1):​c.1029_1031dupAGC​(p.Ala344dup) variant causes a disruptive inframe insertion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A344A) has been classified as Pathogenic. The gene KCNQ1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 disruptive_inframe_insertion, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.38
• Publications: 0 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

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 6 ACMG points.

• PM1: In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000218.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-2583540-C-CCAG is Pathogenic according to our data. Variant chr11-2583540-C-CCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 200885.

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.1029_1031dupAGC	p.Ala344dup	disruptive_inframe_insertion splice_region	Exon 7 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1029_1031dupAGC	p.Ala344dup	disruptive_inframe_insertion splice_region	Exon 7 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.759_761dupAGC	p.Ala254dup	disruptive_inframe_insertion splice_region	Exon 8 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.1029_1031dupAGC	p.Ala344dup	disruptive_inframe_insertion splice_region	Exon 7 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.648_650dupAGC	p.Ala217dup	disruptive_inframe_insertion splice_region	Exon 7 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1026_1028dupAGC	p.Ala343dup	disruptive_inframe_insertion splice_region	Exon 7 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794728559; hg19: chr11-2604770;