rs1800171

Positions:

• chr11-2583545-G-A
• chr11-2583545-G-C
• chr11-2583545-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1032G>A​(p.Ala344Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,609,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A344A) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 1.79

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2583545-G-A is Pathogenic according to our data. Variant chr11-2583545-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583545-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1032G>A	p.Ala344Ala	splice_region_variant, synonymous_variant	7/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1032G>A	p.Ala344Ala	splice_region_variant, synonymous_variant	7/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.651G>A	p.Ala217Ala	splice_region_variant, synonymous_variant	7/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.771G>A	p.Ala257Ala	splice_region_variant, synonymous_variant	8/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.588G>A	p.Ala196Ala	splice_region_variant, synonymous_variant	3/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251186 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

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: 6.86e-7 AC: 1 AN: 1456938 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725086

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 07, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:10477533, 21810471). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:10477533, 21810471, 27485560, 29255176, 31589614, 31737537). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID:10477533).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Jan 12, 2024	- -
Pathogenic, no assertion criteria provided	research	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 (MIM#609621), while dominant negative and loss of function variants can cause Long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and 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 characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic mutations (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews, OMIM). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. This variant has been shown to result in several splicing errors, including the skipping of exon 7, exon 8, or both exon 7 and 8. Quantitative analysis confirmed only 55% of wildtype transcript remained (PMID: 21810471). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Multiple pathogenic variants at the same residue have been reported as pathogenic, and it is described as the 2nd most mutated codon (Decipher, PMID: 10477533). (SP) 0703 - Other synonymous splice variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes at the same nucleotide position (c.1032G>C, c.1032G>T) have been reported as pathogenic, likely pathogenic and in a family with LQTS (ClinVar, PMID: 10477533). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and in multiple families with LQTS (ClinVar, PMID: 21810471, PMID: 10477533). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); A different nucleotide change at the same position (c.1032 G>C, A344A) has also been reported to affect splicing and was found to segregate with a LQTS phenotype in a multi-generation family (Murray et al., 1999); Reported in ClinVar as pathogenic (ClinVar Variant ID# 3135; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21810471, 29857160, 9570196, 26318259, 10973849, 19716085, 29497013, 10477533, 22629021, 9654228, 26118460, 29255176, 27485560, 28438721, 17292394, 31737537, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	The KCNQ1 c.1032G>A; p.Ala344= variant (rs1800171) is reported in the literature in individuals and families affected with long QT syndrome (Gao 2012, Kanters 1998, Tsuji 2007, Tsuji-Wakisaka 2011). This variant is also reported in ClinVar (Variation ID: 3135). It is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant in the last nucleotide of exon 7, and mRNA assays have shown this variant causes exon skipping (Tsuji 2007, Tsuji-Wakisaka 2011). Based on available information, this variant is considered to be pathogenic. References: Gao Y et al. Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome. J Cardiovasc Dis Res. 2012 Apr;3(2):67-75. PMID: 22629021. Kanters JK et al. Novel donor splice site mutation in the KVLQT1 gene is associated with long QT syndrome. J Cardiovasc Electrophysiol. 1998 Jun;9(6):620-4. PMID: 9654228. Tsuji K et al. Mechanistic basis for the pathogenesis of long QT syndrome associated with a common splicing mutation in KCNQ1 gene. J Mol Cell Cardiol. 2007 Mar;42(3):662-9. PMID: 17292394. Tsuji-Wakisaka K et al. Identification and functional characterization of KCNQ1 mutations around the exon 7-intron 7 junction affecting the splicing process. Biochim Biophys Acta. 2011 Nov;1812(11):1452-9. PMID: 21810471. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Long QT syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	The c.1032G>A (p.Ala344=) variant in the KCNQ1 gene has been reported in multiple individuals with long QT syndrome and Jervell and Lange-Nielsen syndrome (PMID: 17292394, 9654228, 10973849, 29857160, 32893267). RNA studies have shown that this variant causes exon 7 skipping (PMID: 21810471). This variant has been demonstrated to disrupt protein function (PMID: 17292394). This variant has been reported in ClinVar as pathogenic (ID: 3135). The overall frequency of this variant in the population database (gnomAD) is 1/251186 chromosomes. Based on this evidence, the c.1032G>A (p.Ala344=) variant in the KCNQ1 gene has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change affects codon 344 of the KCNQ1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KCNQ1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs1800171, gnomAD 0.0009%). This variant has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 9654228, 10973849, 21810471, 22629021). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3135). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 21810471). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2019	Variant summary: KCNQ1 c.1032G>A (p.Ala344Ala) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. At least two publications reported experimental evidence that this variant affects mRNA splicing (Murray 1999, Tsuji-Wakisaka 2011), causing a partial exon skipping, decreasing the wild type mRNA level to about 55% (Tsuji-Wakisaka 2011). The variant allele was found at a frequency of 4e-06 in 251186 control chromosomes (gnomAD). c.1032G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (Kanters 1998, Li 1998, Murray 1999, Tsuji-Wakisaka 2011), and in two large families the variant co-segregated with the disease (Li 1998, Murray 1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated significant reduction in currents compared to control (Tsuji-Wakisaka 2011). 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 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, University of Leuven

Feb 09, 2017

ACMG score pathogenic -

Beckwith-Wiedemann syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 16, 2018

The p.Ala344Ala variant in KCNQ1 has been reported in >20 heterozygous individuals with Long QT syndrome (LQTS) and in one compound heterozygous individual with Jervell and Lange-Nielsen syndrome (JLNS). It segregated with LQTS in > 10 relatives from multiple families (Kanters 1998, Struijk 2006, Tsuji 2007, Gao 2012, Itoh 2015, Vyas 2016, Robyns 2017). This variant has also been reported in ClinVar (Variation ID: 3135) and has been identified in 1/111614 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs1800171). This variant is located at the last base of exon 7, which is part of the 5’ splice region. Computational tools and functional studies using patient mRNAs suggest that the p.Ala344ala variant impacts splicing, resulting mainly in the skipping of exon 7 but other aberrant mRNA transcripts were also reported (Wuriyanghai 2018, Tsuji 2007). In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, predicted impact to the protein, and functional studies. ACMG/AMP criteria applied: PS4, PP1_Strong, PM4, PS3_Moderate, PM2. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2024

The c.1032G>A pathogenic mutation (also known as p.A344A) is located in coding exon 7 of the KCNQ1 gene. This variant results from a G to A substitution at nucleotide position 1032. This nucleotide substitution does not change the amino acid at codon 344. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in multiple families with long QT syndrome (LQTS) and Jervell and Lange-Nielsen syndrome, including at least one reported de novo case of LQTS (Kanters JK et al. J. Cardiovasc. Electrophysiol., 1998 Jun;9:620-4; Murray A et al. Circulation, 1999 Sep;100:1077-84; Tsuji-Wakisaka K et al. Biochim. Biophys. Acta, 2011 Nov;1812:1452-9; Gao Y et al. J Cardiovasc Dis Res, 2012 Apr;3:67-75). RNA studies have demonstrated that this alteration leads to exon skipping with the loss of exon 7 as the most frequently observed effect (Murray A et al. Circulation, 1999 Sep;100:1077-84; Tsuji-Wakisaka K et al. Biochim. Biophys. Acta, 2011 Nov;1812:1452-9). In addition, in vitro functional studies have shown significant suppression of potassium channel currents (Tsuji-Wakisaka K et al. Biochim. Biophys. Acta, 2011 Nov;1812:1452-9). This nucleotide position is not well conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 15
DS_DL_spliceai		0.38		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800171; hg19: chr11-2604775;