rs1435990592

chr11-2445294-TCCCCGGCCGCG-T

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.200_210del(p.Pro67ArgfsTer214) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.827

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 11-2445294-TCCCCGGCCGCG-T is Pathogenic according to our data. Variant chr11-2445294-TCCCCGGCCGCG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2445294-TCCCCGGCCGCG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.200_210del	p.Pro67ArgfsTer214	frameshift_variant	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.200_210del	p.Pro67ArgfsTer214	frameshift_variant	1/15
KCNQ1	NM_001406838.1	c.200_210del	p.Pro67ArgfsTer212	frameshift_variant	1/11
KCNQ1	NM_001406837.1	c.-163_-153del		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.200_210del	p.Pro67ArgfsTer214	frameshift_variant	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000646564.2	c.200_210del	p.Pro67ArgfsTer212	frameshift_variant	1/11
KCNQ1	ENST00000496887.7	c.24-85_24-75del		intron_variant		5
KCNQ1	ENST00000345015.4			upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.03e-7 AC: 1 AN: 1244822 Hom.: 0 AF XY: 0.00000164 AC XY: 1 AN XY: 610262

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: 9.90e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2021	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; Identified in patients with Long QT syndrome referred for testing at GeneDx and in the published literature (Kapplinger et al., 2009).; Not observed at significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 19716085, 27535533, 26582918) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 30, 2021	- -

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Aug 01, 2023

- -

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

Dec 05, 2021

- -

KCNQ1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2024

The KCNQ1 c.200_210del11 variant is predicted to result in a frameshift and premature protein termination (p.Pro67Argfs*214). This variant has been reported to be causative for long QT syndrome (described as 200_210delCGGCCGCGCCC (S66fs+213X) in Table S1, Kapplinger et al. 2009. PubMed ID: 19716085). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in KCNQ1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

This sequence change creates a premature translational stop signal (p.Pro67Argfs*214) 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). 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: 19716085). ClinVar contains an entry for this variant (Variation ID: 449221). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2018

The c.200_210del11 pathogenic mutation, located in coding exon 1 of the KCNQ1 gene, results from a deletion of 11 nucleotides at nucleotide positions 200 to 210, causing a translational frameshift with a predicted alternate stop codon (p.P67Rfs*214). In a study of long QT syndrome clinical genetic testing, this alteration (also described as S66fs+213X) was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). In addition to the clinical data presented in the literature, 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1435990592; hg19: chr11-2466524;