rs397508112

chr11-2570637-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000218.3(KCNQ1):c.488del(p.Leu163ArgfsTer74) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000548 in 1,460,366 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: 0.0000055 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.81

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-2570637-CT-C is Pathogenic according to our data. Variant chr11-2570637-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570637-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.488del	p.Leu163ArgfsTer74	frameshift_variant	3/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.488del	p.Leu163ArgfsTer74	frameshift_variant	3/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.107del	p.Leu36ArgfsTer74	frameshift_variant	3/16	1
KCNQ1	ENST00000496887.7	c.227del	p.Leu76ArgfsTer74	frameshift_variant	4/16	5
KCNQ1	ENST00000646564.2	c.478-12797del		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460366 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726592

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2023	Not observed 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: 15466642, 15840476, 19716085, 19841300, 22677073, 31447099, 30122538, 33087929, 34319147) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 01, 2021	- -

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

May 24, 2017

The c.488del (p.Leu163Argfs*74) variant in the KCNE1 gene has been reported in a patient from a cohort of 388 patients referred for LQTS genetic testing with a family history of a first degree relative with a cardiac event during swimming [reported as V162fs in PMID 15840476, 15840476]. This variant has not been observed in the ExAC database but has been assessed in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/53050). This one bp deletion in exon 3 results in a frameshift and the creation of a premature stop codon, and is predicted to result in a loss of function of KCNQ1. This variant is thus classified as pathogenic -

Jervell and Lange-Nielsen syndrome;C1141890:Congenital long QT syndrome;C5680250:Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 02, 2015

The p.Leu163fs variant in KCNQ1 has been previously reported in at least 1 indiv idual with long QT syndrome and is absent from large population databases (Choi 2004, Tester 2005, Kapplinger 2009). This variant is predicted to cause a frames hift, which alters the protein's amino acid sequence beginning at codon 163 and leads to a premature stop codon 74 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Loss of function variants in KCNQ1 lead to Jervell and Lange-Nielsen syndrome (JLNS) in compound heterozy gous and homozygous individuals, while dominant-negative and loss-of-function va riants in KCNQ1 have been shown to cause dominantly inherited long QT syndrome 1 (also known as Romano-Ward syndrome)in heterozygous individuals. In summary, al though additional studies are required to fully establish its clinical significa nce, this variant meets our criteria to be classified as likely pathogenic (http ://www.partners.org/personalizedmedicine/LMM) based upon its impact to the prote in. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 17, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53050). This variant is also known as L163FS/X236. This premature translational stop signal has been observed in individuals with sudden unexplained death (PMID: 22677073). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu163Argfs*74) 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). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2020

The c.488delT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of one nucleotide at position 488, causing a translational frameshift with a predicted alternate stop codon (p.L163Rfs*74). This mutation has been reported in patients referred for long QT syndrome clinical genetic testing; however, clinical details are limited (Tester DJ et al. Heart Rhythm. 2005;2:507-17; Kapplinger JD et al. Heart Rhythm. 2009;6(9):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

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: rs397508112; hg19: chr11-2591867;