11-2847858-GC-GCC

Variant names:

• chr11-2847858-G-GC
• rs397508104
• NM_000218.3:c.1893dupC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1893dupC​(p.Arg632GlnfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,574,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: -0.797

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-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0675 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 11-2847858-G-GC is Pathogenic according to our data. Variant chr11-2847858-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1893dupC	p.Arg632GlnfsTer20	frameshift_variant	Exon 16 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1893dupC	p.Arg632GlnfsTer20	frameshift_variant	Exon 16 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152122 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: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000225 AC: 32 AN: 1422690 Hom.: 0 Cov.: 31 AF XY: 0.0000241 AC XY: 17 AN XY: 704070

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.0000251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.000122

Gnomad4 NFE exome AF: 0.00000916

Gnomad4 OTH exome AF: 0.0000510

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:6

Jan 30, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.1893dup (p.Arg632Glnfs*20) variant in the KCNQ1 gene has been reported in 1/93 unrelated LQTS patients [PMID:10024302] while observed with extremely low allele frequency in general population according to gnomad database. This variant has also been reported in trans with an exon7-10 deletion of KCNQ1 in 2 LQTS brothers while both parents are normal carriers. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidences, c.1893dup (p.Arg632Glnfs*20) variant in the KCNQ1 gene is classified as pathogenic. -

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PVS1_MOD,PS3_MOD -

Jan 15, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 01, 2023

Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 28, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

Dec 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also reported as insC1893-1894 or c.1886_1887insC due to alternate nomenclature, and identified in patients with LQTS (PMID: 10024302, 10973849, 16981927, 19716085, 23098067, 32470535, 31737537, 32383558); Observed in large population cohorts (gnomAD; internal data); Published functional studies suggest a damaging effect: trafficking defect, complete loss of electrophysiological function of the KvLQT1 channel (PMID: 19825999); Frameshift variant predicted to result in protein truncation, as the last 45 amino acids are replaced with 19 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 31447099, 10973849, 19716085, 23098067, 23158531, 22727609, 23631430, 19825999, 28798025, 31589614, 34691145, 34505893, 10024302, 32470535, 16981927, 33498651, 32383558, Baye_Article_2022, 31737537, 25187895) -

Jul 06, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PM6, PS3, PS4_moderate, PVS1_strong -

Jan 01, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2022

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNQ1 c.1893dupC (p.Arg632GlnfsTer20) variant results in the duplication of a nucleotide at position c.1893, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. Across a selection of the available literature, the p.Arg632GlnfsTer20 variant has been reported in a heterozygous state in at least two individuals with either confirmed or suspected long QT syndrome and in an asymptomatic parent of one of these individuals (PMID: 10024302; PMID: 19716085). Additionally, this variant has been detected in a homozygous state in two individuals with prolonged QT intervals and syncope, while the asymptomatic parents of these individuals were all heterozygous (PMID: 16981927; PMID: 23098067). At least three additional individuals have been reported with a second loss of function variant in KCNQ1, all with prolong QT intervals in addition to a history of cardiac arrest and a positive family history, or a diagnosis of Jervell and Lange-Nielsen syndrome, each in one individual (PMID: 23631430; PMID: 25187895). This variant is reported in the Genome Aggregation Database in three alleles at a frequency of at a frequency of 0.000622 in the South Asian population (version 3.1.2). Experimental evidence in HEK293 and CHO-1 cells show the p.Arg632GlnfsTer20 variant to result in protein trafficking defects and significantly reduced potassium channel activity (PMID: 19825999). Based on the available evidence, the c.1893dupC (p.Arg632GlnfsTer20) variant is classified as likely pathogenic for KCNQ1-related disorders, with reduced penetrance and either a dominant or recessive mode of inheritance. -

Long QT syndrome Pathogenic:3

Aug 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts one nucleotide in exon 16 of the KCNQ1 gene, creating a frameshift in the last exon. This variant is also known as c.1893_1894insC and P631fs/19 in the literature. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. A functional study has shown that this variant causes protein trafficking defects, and the mutant protein is retained in the endoplasmic reticulum and unable to reach the cell surface (PMID: 19825999). As a result, the cells show severely decreased potassium currents (PMID: 19825999, 33498651). This variant has been reported in multiple individuals affected with monoallelic and biallelic forms of long QT syndrome (PMID: 10024302, 19825999, 23098067, 23631430, 25187895, 33498651). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg632Glnfs*20) in the KCNQ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the KCNQ1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with long QT syndrome, Jervell and Lange-Nielsen syndrome and recessive Romano–Ward syndrome (PMID: 10024302, 16981927, 19825999, 23098067, 23631430, 25187895). This variant is also known as 1893insC, insC1893–1894 (P631fs/19), 1893insC P631+19X and p.G629fs. ClinVar contains an entry for this variant (Variation ID: 53027). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects KCNQ1 function (PMID: 19825999). For these reasons, this variant has been classified as Pathogenic. -

Aug 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in KCNQ1 is a frameshift variant that may cause a premature stop codon, p.(Arg632Glnfs*20), that is predicted to escape nonsense-mediated decay and remove <10% of the protein in a gene where loss-of-function is an established disease mechanism (PMID: 11226272, 23098067, 26669661, 29532034). The highest population minor allele frequency in the population database gnomAD v4.1 is 0.02% (14/86,106 alleles) in the South Asian population, consistent with a recessive disease. This variant has been detected compound heterozygous with a second pathogenic allele and homozygous in multiple individuals with long QT syndrome (mainly without deafness) and a recessive segregation with disease has been reported in one family (PMID: 16981927, 23098067, 23631430, 25187895, 32470535, 33498651). Heterozygous individuals have largely been reported as unaffected (PMID: 23158531, 30919684, 31696929, 32383558, 34691145). Functional studies suggest the variant only alters cardiac channel function in a homomeric state, supportive of a recessive inheritance trait (PMID: 33498651). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Moderate, PM3_VeryStrong, PP1, PS3_Supporting. -

Congenital long QT syndrome Pathogenic:1

May 03, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiovascular phenotype Pathogenic:1

Nov 22, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1893dupC variant, located in coding exon 16 of the KCNQ1 gene, results from a duplication of C at nucleotide position 1893, causing a translational frameshift with a predicted alternate stop codon (p.R632Qfs*20). This frameshift occurs at the 3' terminus of KCNQ1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 45 amino acids of the protein. However, frameshifts are typically deleterious in nature, and functional in vitro analyses have suggested the truncated protein encoded by this frameshift is mislocalized in cells as a result of a trafficking defect and newly generated endoplasmic reticulum retention signals in the additional amino acids at the 3' terminus (Sato A et al. J Biol Chem. 2009;284:35122-33). Another in vitro study has reported this variant to result in significantly reduced channel current in the homozygous state and some reduction in current in the heterozygous state, where expression with KCNE1 appeared to rescue the effect seen in only the heterozygous state (Oertli A et al. Int J Mol Sci. 2021 Jan;22(3)). This variant has been previously reported in several individuals from long QT syndrome (LQTS) cohorts and in cohorts not selected for the presence of LQTS; however, clinical details were limited in some studies (Neyroud N et al. Circ Res. 1999;84:290-7; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Crotti L et al. J Am Coll Cardiol. 2012;60:2515-24; Marschall C. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298; Zouk et al. Am J Hum Genet. 2019 09;105(3):588-605; Westphal DS. Mol Genet Genomic Med. 2020 09;8(9):e1300). Additionally, this variant has been detected in the homozygous state and in the compound heterozygous state in conjunction with other alterations in KCNQ1 in individuals with prolonged QT intervals. Most, but not all, of these individuals were described to have normal hearing. In these families, this variant was detected in the heterozygous state in clinically unaffected relatives, suggesting co-segregation with incomplete penetrance (Novotny T et al. Pacing Clin Electrophysiol. 2006;29:1013-5; Sato A et al, 2009; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61; Sung JY et al. Ann Lab Med. 2014;34:395-8; Oertli A et al. Int J Mol Sci. 2021 Jan;22(3)). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiac arrhythmia Pathogenic:1

Dec 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts one nucleotide in exon 16 of the KCNQ1 gene, creating a frameshift in the last exon. This variant is also known as c.1893_1894insC and P631fs/19 in the literature. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. A functional study has shown that this variant causes protein trafficking defects, and the mutant protein is retained in the endoplasmic reticulum and unable to reach the cell surface (PMID: 19825999). As a result, the cells show severely decreased potassium currents (PMID: 19825999, 33498651). This variant has been reported in multiple individuals affected with monoallelic and biallelic forms of long QT syndrome (PMID: 10024302, 19825999, 23098067, 23631430, 25187895, 33498651). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -

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: rs397508104; hg19: chr11-2869088;