11-2661960-G-T

Position:

• chr11-2661960-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PP3_Moderate PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1394-1G>T variant causes a splice acceptor 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 splice_acceptor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.59

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-2661960-G-T is Pathogenic according to our data. Variant chr11-2661960-G-T is described in ClinVar as [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/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1394-1G>T		splice_acceptor_variant		ENST00000155840.12
KCNQ1OT1	NR_002728.3	n.38039C>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1394-1G>T		splice_acceptor_variant		1	NM_000218.3	P1
KCNQ1OT1	ENST00000710656.1	n.376-20845C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251392 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135894

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: 52 AN: 1461854 Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28 AN XY: 727222

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.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: 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	Jul 24, 2023	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in an individual diagnosed with severe LQTS who also harbored a frameshift variant in the KCNH2 gene (Chung et al., 2007); This variant is associated with the following publications: (PMID: 25525159, 19862833, 9323054, 23631430, 26318259, 34135346, 34319147, 17905336, 33087929) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 31, 2013	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. -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 01, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 10, 2023	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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2021

The c.1394-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from 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). In addition to the clinical data presented in the literature, 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

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 30, 2023

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, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	D;D
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

Other links and lift over

dbSNP: rs775537394; hg19: chr11-2683190;