rs794728562

Positions:

• chr11-2776984-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1686del variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 splice_acceptor
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.94

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.018053375 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: gtctgtgtccttctctccAGctg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-2776984-AG-A is Pathogenic according to our data. Variant chr11-2776984-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2776984-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1686del		splice_acceptor_variant		ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1686del		splice_acceptor_variant		1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.1305del		splice_acceptor_variant		1
KCNQ1	ENST00000496887.7	c.1329del		splice_acceptor_variant		5
KCNQ1	ENST00000646564.2	c.1146del		splice_acceptor_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461768 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 115 amino acids are replaced with 30 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 23631430) -

Congenital long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 07, 2020

The p.Arg562SerfsX31 variant in KCNQ1 has been reported in 1 individual with suspected long QT syndrome (LQTS; Lieve 2013) was absent from large population studies. It has also been reported by other clinical laboratories in ClinVar (Variation ID# 200888). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 562 and leads to a premature termination codon 31 amino acids downstream. The location of this premature termination codon is within the terminal 50 bases of the second to last exon and is therefore more likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~13% of the coding region, with 85 amino acids removed. Truncating variants in KCNQ1 downstream of this position have been reported in individuals with LQTS. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PVS1_Strong, PM2. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 29, 2023

This sequence change creates a premature translational stop signal (p.Arg562Serfs*31) in the KCNQ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the KCNQ1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 200888). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the KCNQ1 protein in which other variant(s) (p.Arg632Glnfs*20) have been determined to be pathogenic (PMID: 10024302, 23098067, 23631430, 25187895). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.1686delG pathogenic mutation, located in coding exon 14 of the KCNQ1 gene, results from a deletion of one nucleotide at nucleotide position 1686, causing a translational frameshift with a predicted alternate stop codon (p.R562Sfs*31). This alteration occurs at the 3' terminus of theKCNQ1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 12% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in a long QT syndrome genetic testing cohort (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 05, 2023

This variant causes a deletion of 1 nucleotide in exon 16 of the KCNQ1 gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product with the last 115 amino acids replaced with 30 different amino acids. The variant is expected to alter the sequence of C-terminal cytoplasmic domain (a.a. 588-622), which is important for protein function (PMID: 10654932, 18165683, 19693805, 19825999). This variant has been reported in an individual affected with long QT syndrome (PMID: 23631430). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.93		Position offset: 3
DS_AL_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728562; hg19: chr11-2798214;