rs397508104

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-2847858-GC-G
• chr11-2847858-GC-GCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1893delC​(p.Arg632GlufsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000698 in 1,574,920 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P631P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.797
• Publications: 12 publications found

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

Our verdict: Pathogenic. The variant received 12 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. There are 5 pathogenic variants in the truncated region.
• PP5: Variant 11-2847858-GC-G is Pathogenic according to our data. Variant chr11-2847858-GC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53026.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.1893delC	p.Arg632GlufsTer34	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.1893delC	p.Arg632GlufsTer34	frameshift_variant	Exon 16 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000490 AC: 9 AN: 183570 AF XY: 0.0000704

Gnomad AFR exome AF: 0.0000972

Gnomad AMR exome AF: 0.0000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000703 AC: 10 AN: 1422680 Hom.: 0 Cov.: 31 AF XY: 0.00000994 AC XY: 7 AN XY: 704064

African (AFR) AF: 0.00 AC: 0 AN: 32656

American (AMR) AF: 0.0000501 AC: 2 AN: 39900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25420

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37502

South Asian (SAS) AF: 0.00 AC: 0 AN: 81288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000549 AC: 6 AN: 1092160

Other (OTH) AF: 0.0000170 AC: 1 AN: 58838

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

Aug 23, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 28, 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.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. -

Long QT syndrome 1 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Pathogenic:1

Jan 05, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Cardiac arrhythmia Pathogenic:1

Jun 29, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.80
Mutation Taster		=9/191	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397508104; hg19: chr11-2869088;