11-2588718-GAAAA-GAAAAA

Position:

• chr11-2588718-GAAAA-GAAAAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1265dupA​(p.Phe423fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.91

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2588718-G-GA is Pathogenic according to our data. Variant chr11-2588718-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1265dupA	p.Phe423fs	frameshift_variant	10/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1265dupA	p.Phe423fs	frameshift_variant	10/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.884dupA	p.Phe296fs	frameshift_variant	10/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.908dupA	p.Phe304fs	frameshift_variant	10/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.725dupA	p.Phe243fs	frameshift_variant	5/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461222 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726896

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: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 08, 2022	The one nucleotide duplication [c.1265dup p.(Phe423ValfsTer40)] identified in exon 10 (of 16) of KCNQ1 alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant as well as an adjacent one nucleotide duplication with the same predicted effect on protein [c.1266dupG p.(Phe423ValfsTer40)] have been reported in individuals affected with long QTsyndrome [PMID:15840476, 24912595]. The c.1265dup variant identified here has been reported in ClinVar database as Pathogenic/Likely Pathogenic[Variation ID: 52974], and is absent from population databases (gnomADv2, gnomADv3, TOPMed Freeze 8) suggesting it is not a common benign variant inpopulations represented in those databases. Based on the available evidence, the c.1265dup p.(Phe423ValfsTer40) variant identified in the KCNQ1 gene is reported as Pathogenic. -

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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 18, 2021

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 23, 2022

Reported in association with Long QT syndrome (Lupoglazoff et al., 2004; Tester et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19862833, 15840476, 26669661, 14998624) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This sequence change creates a premature translational stop signal (p.Phe423Valfs*40) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Long QT syndrome (PMID: 15840476, 34860437). This variant is also known as ins A 1265–1266, K422fs/39*. ClinVar contains an entry for this variant (Variation ID: 52974). For these reasons, this variant has been classified as Pathogenic. -

Ear malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2021

The c.1265dupA pathogenic mutation, located in coding exon 10 of the KCNQ1 gene, results from a duplication of A at nucleotide position 1265, causing a translational frameshift with a predicted alternate stop codon (p.F423Vfs*40). This mutation (also referred to as g.1258 ins A and ins A 1265–1266) has been reported in association with long QT syndrome (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Lupoglazoff JM et al. J Am Coll Cardiol, 2004 Mar;43:826-30). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Jervell and Lange-Nielsen syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: PVS1_Strong, PS4_Moderate, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508083; hg19: chr11-2609948;