11-2661960-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000218.3(KCNQ1):c.1394-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000356 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 splice_acceptor, intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.59

Variant links:

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]

KCNQ1 links:

KCNQ1OT1 (HGNC:6295): (KCNQ1 opposite strand/antisense transcript 1) Human chromosomal region 11p15.5 contains two clusters of epigenetically-regulated genes that are expressed from only one chromosome in a parent-of-origin manner. Each cluster, or imprinted domain, is regulated by a functionally independent imprinting control region (ICR). The human CDKN1C/KCNQ1OT1 domain is regulated by an ICR located in an intron of KCNQ1, and contains at least eight genes that are expressed exclusively or preferentially from the maternally-inherited allele. The DNA of the ICR is specifically methylated on the maternally-inherited chromosome, and unmethylated on the paternally-inherited chromosome. The ICR contains the promoter of the KCNQ1OT1 gene that is exclusively expressed from the paternal allele. The KCNQ1OT1 transcript is the antisense to the KCNQ1 gene and is a unspliced long non-coding RNA. It interacts with chromatin and regulates transcription of multiple target genes through epigenetic modifications. The transcript is abnormally expressed from both chromosomes in most patients with Beckwith-Wiedemann syndrome, and the transcript also plays an important role in colorectal carcinogenesis. [provided by RefSeq, Apr 2012]

KCNQ1OT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.3, offset of 4, new splice context is: cacactttctcctcattaAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 11-2661960-G-T is Pathogenic according to our data. Variant chr11-2661960-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2661960-G-T is described in Lovd as [Pathogenic]. Variant chr11-2661960-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.1394-1G>T		splice_acceptor_variant, intron_variant	Intron 10 of 15	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 link	c.1394-1G>T		splice_acceptor_variant, intron_variant	Intron 10 of 15	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251392

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727222

show subpopulations

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:

0.0000468

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Pathogenic:3

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 10 of the KCNQ1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This variant is present in population databases (rs775537394, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with long QT syndrome (PMID: 17905336, 23631430, 26318259; Invitae). This variant is also known as IVS10-1G>T. ClinVar contains an entry for this variant (Variation ID: 200847). 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. -

Sep 01, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The KCNQ1 c.1394-1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was found in the control population dataset of ExAC in 1/121208 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). This variant was reported in multiple patients with LQTS in the literature (Chung_2007, Lieve_2013, Ruwald_2016) and was stated as segregating with LQTS in a family (Stanford Center for Inherited Cardiovascular Disease). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to T nucleotide substitution at the -1 position of intron 10 (also known as IVS10-1G>T) of the KCNQ1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been observed in multiple individuals affected with or suspected of having long QT syndrome (PMID: 17905336, 23631430, 26318259, 38489124, ClinVar SCV000280145.1, communication with external laboratories: SCV000752693.7, SCV000234493.16, SCV000738035.4). It has been reported that this variant segregates with disease in at least one of the families (communication with an external laboratory ClinVar SCV000234493.16). This variant has also been reported in a healthy individual aged 70 years or older without a history of coronary heart disease (PMID: 34135346). This variant has been identified in 1/251392 chromosomes 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. -

not provided

Pathogenic:2

Oct 31, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 IVS10-1G>T (c.1394-1G>T) Based on the data reviewed below, we consider it likely disease-causing. This variant has been seen in at least one published case in the literature. We have also found it segregating with LQTS in one family at our center. Chung et al. 2007 identified this splice variant in addition to a frameshift insertion in KCNH2 in a patient with “severe LQTS”. In terms of clinical details, this patient was Caucasian, had a personal history of syncope and a family history of SCD in a first degree relative, and had a QTc of 520 ms. Her diagnosis was described as “LQT1/LQT2”). It was absent from 50 control individuals in this study. This variant is very likely to disrupt normal splicing, as it changes the last base of intron 10 from a G to a T thus destroying the canonical G nucleotide of the splice acceptor site. There are several splice, nonsense and frameshift variants that have been associated with LQTS in the literature, including nearby splicing variants also in the c-terminus (922-1G>C; 1251+2T>C; 1514+1G>A). In total, this variant has not been seen in approximately 6,650 publicly available population and laboratory controls (including ~6,500 individuals of African American and European ancestry from NHLBI ESP dataset; 100 Caucasian individuals from GeneDx; and 50 individuals from Chung et al. 2007). There is a variant involving this same splice acceptor site seen in 6 individuals in ESP, however it is at the -8 position (thus unlikely to have the same effect as changing the canonical splice acceptor site). This variant has also not been observed in the 1000Genomes dataset or dbSNP as of October 31, 2013. This variant is currently present in HGMD and LOVD as a disease-causing mutation on the basis of the Chung et al. 2007 variant. -

Dec 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual diagnosed with severe LQTS who also harbored a frameshift variant in the KCNH2 gene (PMID: 17905336); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 19862833, 9323054, 23631430, 26318259, 34135346, 34319147, 33087929, 17905336) -

Long QT syndrome 1

Pathogenic:1

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome 2 (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome 1 (LQTS, MIM#192500), familial atrial fibrillation 3 (MIM#607554) as well as Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterised by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 20301308). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 1 heterozygote, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Other splice variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two alternative canonical splice variants, c.1394-1G>C and c.1394-2A>G, have been reported as pathogenic in ClinVar. Additionally, the c.1394-2A>G variant has been reported as homozygous and heterozygous in related individuals with JLNS and LQTS-1, respectively (PMID: 30099333). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant, also referred to as IVS10-1G>T, has been classified as likely pathogenic/pathogenic by several clinical laboratories, and has been observed in an internal VCGS patient with LQTS (ClinVar, VCGS). It has also been reported in the literature in individuals with LQTS (PMIDs: 17905336, 26318259, 33029862). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype

Pathogenic:1

Jul 17, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1394-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide before coding exon 11 of the KCNQ1 gene. This alteration (also referred to as IVS10-1G>T) has been detected in a subject with long QT syndrome (LQTS) who also carried a second frameshift alteration in KCNH2 (Chung SK et al. Heart Rhythm, 2007 Oct;4:1306-14). This alteration was also reported in additional LQTS cohorts; however, clinical details were limited (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Ruwald MH et al. Heart Rhythm. 2016 Jan;13(1):122-31). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Cardiac arrhythmia

Pathogenic:1

May 30, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.93

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.78

Position offset: 5

DS_AL_spliceai

0.99

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over