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

dbSNP: rs397508104

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046039	SCV000074052	pathogenic	Long QT syndrome	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg632Glufs*34) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). 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 individual(s) with long QT syndrome (PMID: 16414944, 22739119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53026). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001841641	SCV001355370	likely pathogenic	Cardiac arrhythmia	2023-06-29	criteria provided, single submitter	clinical testing	This variant deletes a single nucleotide in the last exon 16 of the KCNQ1 gene, creating a frameshift at codon 632 followed by addition of 33 new amino acids and a stop codon. As a result, this variant alters the cytoplasmic C-terminal region of the KCNQ1 protein. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (PMID: 22739119). This variant has been reported in 2 or more individuals affected with long QT syndrome (PMID: 16414944, 22739119). 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 Likely Pathogenic.
GeneDx	RCV001787845	SCV002031097	likely pathogenic	not provided	2025-01-05	criteria provided, single submitter	clinical testing	Identified in patients with Long QT syndrome referred for genetic testing at GeneDx and in published literature (PMID: 22739119, 16414944, 26669661); Published functional studies using iPSCs and HEK293 cells suggest that that this variant has a dominant negative effect due to a trafficking deficiency (PMID: 22739119); Frameshift variant predicted to result in abnormal protein length as the last 45 amino acids are replaced with 33 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 19825999, 16414944, 27026928, 27110425, 26669661, 30609406, 24657289, 27009425, 23444871, 29976690, 32231684, 34691145, 22739119)
All of Us Research Program, National Institutes of Health	RCV000046039	SCV004836500	likely pathogenic	Long QT syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This variant deletes a single nucleotide in the last exon 16 of the KCNQ1 gene, creating a frameshift at codon 632 followed by addition of 33 new amino acids and a stop codon. As a result, this variant alters the cytoplasmic C-terminal region of the KCNQ1 protein. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (PMID: 22739119). This variant has been reported in 2 or more individuals affected with long QT syndrome (PMID: 16414944, 22739119). 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 Likely Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV004576918	SCV005060971	pathogenic	Long QT syndrome 1		criteria provided, single submitter	clinical testing	The frameshift variant c.1893del(p.Arg632GlufsTer34) in the KCNQ1 gene has been reported previously in a heterozygous state in individuals affected with Long QT syndrome. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (Egashira et al., 2012; Napolitano et al., 2005). This variant is reported with the allele frequency (0.004%) in the gnomAD Exomes. This variant causes a frameshift starting with codon Arginine 632, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 34 of the new reading frame. It is submitted to ClinVar as Pathogenic/ Likely pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.