rs397508075

Positions:

• chr11-2585254-C-T

Variant summary

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

The NM_000218.3(KCNQ1):​c.1075C>T​(p.Gln359Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.39

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 11-2585254-C-T is Pathogenic according to our data. Variant chr11-2585254-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 52950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2585254-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1075C>T	p.Gln359Ter	stop_gained	8/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1075C>T	p.Gln359Ter	stop_gained	8/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.694C>T	p.Gln232Ter	stop_gained	8/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.771+1709C>T		intron_variant		5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.588+1709C>T		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727168

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2023	Nonsense 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: 22956155, 25294783, 21956039, 26370830, 19841300, 29265593, 19716085, 34505893) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 14, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Gln359Stop We classify this variant as likely disease-causing. This nonsense variant has been reported previously in 4 unrelated patients tested for LQTS through the Familion laboratory (Kapplinger et al. 2009). It is also described by Vijayakumar et al. (2014) in a female patient with a QTc of 516 and an ICD (unknown if this patient or a family member was tested at Familion). No segregation analysis is available. Kapplinger et al. report that it was absent from 1300 control individuals (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). This specific variant is not present in the NHLBI ESP. It is predicted to cause loss of normal protein function either due to a prematurely truncated protein or absent protein product due to nonsense mediated mRNA decay. Other nonsense mutations in the KCNQ1 gene have been reported in HGMD in association with LQTS. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 16, 2021	- -

Long QT syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change creates a premature translational stop signal (p.Gln359*) 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, 19841300, 22956155). ClinVar contains an entry for this variant (Variation ID: 52950). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 06, 2023	The c.1075C>T (p.Gln359*) variant in the KCNQ1 gene is expected to introduce a premature translation stop codon resulting in an absent or disrupted protein. This variant has been reported in multiple individuals with long QT syndrome (PMID: 19716085, 19841300, 22956155, 23631430, 27920829, 21956039, 25294783). Loss of function is a known mechanism of disease for LongQT syndrome. Clinvar contains an entry for this variant (Variation ID: 52950). This variant is absent in the general population database (gnomAD). Based on the available evidence c.1075C>T (p.Gln359*) in the KCNQ1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 29, 2020	Variant summary: KCNQ1 c.1075C>T (p.Gln359X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 254048 control chromosomes. c.1075C>T has been reported in the literature in individuals affected with Long QT Syndrome (example, Kapplinger_2009, Kapa_2009, Ware_2013, Lieve_2013, Burns_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Long QT syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 27, 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 22, 2021

- -

KCNQ1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2024

The KCNQ1 c.1075C>T variant is predicted to result in premature protein termination (p.Gln359*). This variant was reported in multiple individuals with long QT syndrome (Kapplinger et al. 2009. PubMed ID: 19716085; Schwartz et al. 2021. PubMed ID: 34505893, supplementary data). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in KCNQ1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2022

The p.Q359* pathogenic mutation (also known as c.1075C>T), located in coding exon 8 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1075. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration has been reported in individuals with long QT syndrome (LQTS) (Kapa S et al. Circulation, 2009 Nov;120:1752-60; Vijayakumar R et al. Circulation, 2014 Nov;130:1936-43). Additionally, this alteration was detected in a pediatric LQTS cohort and in a study of LQTS clinical genetic testing (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Aziz PF et al. Circ Arrhythm Electrophysiol, 2011 Dec;4:867-73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 09, 2022

This variant changes 1 nucleotide in exon 8 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with long QT syndrome (PMID: PMID: 19716085, 19841300, 22956155). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs397508075; hg19: chr11-2606484;