NM_000218.3:c.1893dupC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_StrongPS3PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000074053: Experimental studies have shown that this premature translational stop signal affects KCNQ1 function (PMID:19825999)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R632R) has been classified as Likely benign. The gene KCNQ1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: -0.797

Publications

12 publications found

Variant links:

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 links:

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

KCNQ1-AS1 links:

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ACMG classification

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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 4 pathogenic variants in the truncated region.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000074053: Experimental studies have shown that this premature translational stop signal affects KCNQ1 function (PMID: 19825999).; SCV004836499: 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).; SCV005900415: Functional studies suggest the variant only alters cardiac channel function in a homomeric state, supportive of a recessive inheritance trait (PMID: 33498651).; SCV000234591: Published functional studies suggest a damaging effect: trafficking defect, complete loss of electrophysiological function of the KvLQT1 channel (PMID: 19825999); SCV003802782: 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).; SCV000737795: "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, 2009). 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, 2021)."; SCV001355371: 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).

PP5

Variant 11-2847858-G-GC is Pathogenic according to our data. Variant chr11-2847858-G-GC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 53027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNQ1	NM_000218.3	MANE Select	c.1893dupC	p.Arg632GlnfsTer20	frameshift	Exon 16 of 16	NP_000209.2
KCNQ1	NM_001406836.1		c.1797dupC	p.Arg600GlnfsTer20	frameshift	Exon 15 of 15	NP_001393765.1
KCNQ1	NM_001406837.1		c.1623dupC	p.Arg542GlnfsTer20	frameshift	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1893dupC	p.Arg632GlnfsTer20	frameshift	Exon 16 of 16	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6	TSL:1	c.1512dupC	p.Arg505GlnfsTer20	frameshift	Exon 16 of 16	ENSP00000334497.5	P51787-2
KCNQ1	ENST00000910997.1		c.1890dupC	p.Arg631GlnfsTer20	frameshift	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000817

AC:

AN:

183570

AF XY:

0.0000704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000924

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000225

AC:

AN:

1422690

Hom.:

Cov.:

AF XY:

0.0000241

AC XY:

AN XY:

704070

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32656

American (AMR)

AF:

0.0000251

AC:

AN:

39902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25420

East Asian (EAS)

AF:

0.00

AC:

AN:

37504

South Asian (SAS)

AF:

0.000135

AC:

AN:

81288

European-Finnish (FIN)

AF:

0.000122

AC:

AN:

49206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00000916

AC:

AN:

1092162

Other (OTH)

AF:

0.0000510

AC:

AN:

58838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41526

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome 1 (7)

not provided (4)

Long QT syndrome (3)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.80

Mutation Taster

=23/177

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over