rs397508077

Positions:

• chr11-2585299-CTCAT-C

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.1124_1127del​(p.Ile375ArgfsTer43) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,440 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.70

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 11-2585299-CTCAT-C is Pathogenic according to our data. Variant chr11-2585299-CTCAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 52962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2585299-CTCAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1124_1127del	p.Ile375ArgfsTer43	frameshift_variant	8/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1124_1127del	p.Ile375ArgfsTer43	frameshift_variant	8/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.743_746del	p.Ile248ArgfsTer43	frameshift_variant	8/16	1
KCNQ1	ENST00000496887.7	c.771+1758_771+1761del		intron_variant		5
KCNQ1	ENST00000646564.2	c.588+1758_588+1761del		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251100 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461440 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727066

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2024	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30291343, 26669661, 28532774, 28341588, 36721196, 15840476) -

Cardiovascular phenotype Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Dec 20, 2017	PVS1, PM2, PP5; This variant identified in exon 8 of KCNQ1 involves the deletion of four coding bases (c.1124_1127delTTCA) that results in a shift in the reading frame and introduces a premature termination of the protein 43 amino acids downstream (p.Ile375Ter43). This alteration is absent from healthy populations, and has been classified as a pathogenic alteration by other clinical testing laboratories (SCV000234581.12; SCV000695982.1). No evidence was found to support any of the ACMG Benign criteria; therefore, this alteration meets ACMG guidelines for classification as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2017	Variant summary: The c.1124_1127delTTCA (p.Ile375Argfs) variant in KCNQ1 gene is a frameshift change that results in the loss of the 780 amino acids of CPT (~35%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population datasets of ExAC and gnomAD (120414 and 246038 chrs, respectively). The variant has been reported in at least two LQTS families with maternal lineage of inheritance (Itah, 2016) and another unrelated affected individual (Tester, 2005). In addition, it has been cited as Pathogenic by a reputable databases/clinical laboratories. Taking together, the variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 28, 2024	The c.1124_1127delTTCA (p.I375Rfs*43) alteration, located in exon 8 (coding exon 8) of the KCNQ1 gene, consists of a deletion of 4 nucleotides from position 1124 to 1127, causing a translational frameshift with a predicted alternate stop codon after 43 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/251100) total alleles studied. The highest observed frequency was 0.001% (1/113510) of European (non-Finnish) alleles. This variant has been detected in long QT syndrome cohorts and has been reported as L374/fs43 and L375RfsX43 (Tester, 2005; Itoh, 2016; Ebrahim, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 18, 2023	This sequence change creates a premature translational stop signal (p.Ile375Argfs*43) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52962). This variant is also known as del 1124–1127 L374/fs43*, L375RfsX43. This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 15840476, 28532774). This variant is present in population databases (rs397508077, gnomAD 0.0009%). -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Nov 09, 2023	- -

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Jan 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397508077; hg19: chr11-2606529;