Submissions for variant NM_000218.3(KCNQ1):c.1893dup (p.Arg632fs)

dbSNP: rs397508104

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046040	SCV000074053	pathogenic	Long QT syndrome	2025-01-30	criteria provided, single submitter	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.
GeneDx	RCV000182288	SCV000234591	pathogenic	not provided	2023-12-27	criteria provided, single submitter	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)
Ambry Genetics	RCV000622116	SCV000737795	likely pathogenic	Cardiovascular phenotype	2023-11-22	criteria provided, single submitter	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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000003284	SCV000839973	pathogenic	Long QT syndrome 1	2018-01-30	criteria provided, single submitter	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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000003284	SCV001132519	pathogenic	Long QT syndrome 1	2018-01-15	criteria provided, single submitter	curation
Color Diagnostics, LLC DBA Color Health	RCV001841642	SCV001355371	pathogenic	Cardiac arrhythmia	2023-12-21	criteria provided, single submitter	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195549	SCV001365934	pathogenic	Congenital long QT syndrome	2019-05-03	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
AiLife Diagnostics, AiLife Diagnostics	RCV000182288	SCV002503244	likely pathogenic	not provided	2022-01-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000003284	SCV002581657	pathogenic	Long QT syndrome 1	2022-07-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000182288	SCV003802782	likely pathogenic	not provided	2022-09-19	criteria provided, single submitter	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.
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV000003284	SCV004024179	pathogenic	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000046040	SCV004836499	pathogenic	Long QT syndrome	2024-08-08	criteria provided, single submitter	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182288	SCV005413968	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	PM3, PM6, PS3, PS4_moderate, PVS1_strong
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003284	SCV005900104	likely pathogenic	Long QT syndrome 1	2025-03-04	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PVS1_MOD,PS3_MOD
Molecular Genetics, Royal Melbourne Hospital	RCV000046040	SCV005900415	pathogenic	Long QT syndrome	2024-08-05	criteria provided, single submitter	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.
OMIM	RCV000003284	SCV000023442	pathogenic	Long QT syndrome 1	1999-02-19	no assertion criteria provided	literature only