rs397508073

Variant names:

• chr11-2585243-TGCAGCA-T
• rs397508073
• NM_000218.3:c.1066_1071delCAGCAG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_000218.3(KCNQ1):​c.1066_1071delCAGCAG​(p.Gln356_Gln357del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 8.70
• Publications: 0 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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000218.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-2585243-TGCAGCA-T is Pathogenic according to our data. Variant chr11-2585243-TGCAGCA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52947.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1066_1071delCAGCAG	p.Gln356_Gln357del	conservative_inframe_deletion	Exon 8 of 16	NP_000209.2
	KCNQ1	NM_001406837.1		c.796_801delCAGCAG	p.Gln266_Gln267del	conservative_inframe_deletion	Exon 9 of 17	NP_001393766.1
	KCNQ1	NM_181798.2		c.685_690delCAGCAG	p.Gln229_Gln230del	conservative_inframe_deletion	Exon 8 of 16	NP_861463.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1066_1071delCAGCAG	p.Gln356_Gln357del	conservative_inframe_deletion	Exon 8 of 16	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.685_690delCAGCAG	p.Gln229_Gln230del	conservative_inframe_deletion	Exon 8 of 16	ENSP00000334497.5
	KCNQ1	ENST00000713725.1		c.925_930delCAGCAG	p.Gln309_Gln310del	conservative_inframe_deletion	Exon 7 of 15	ENSP00000519029.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

KCNQ1-related disorder Pathogenic:1

Jun 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KCNQ1 c.1066_1071del6 variant is predicted to result in an in-frame deletion (p.Gln356_Gln357del). This variant was reported to segregate with Long QT syndrome in three individuals in a family (Liang et al. 2003. PubMed ID: 14731347). This variant was also documented in an unrelated individual referred for Long QT syndrome genetic testing (Stattin et al. 2012. PubMed ID: 23098067). This variant was also reported, along with a missense KCNQ1 variant, in an individual with Jervell and Lange-Nielsen syndrome (Cepeda-Nieto et al. 2021. PubMed ID: 34165182). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). However, such prediction programs are imperfect and cannot substitute for mRNA studies. This variant has not been reported in a large population database, indicating this variant is rare. At PreventionGenetics, this variant was found to segregate with Long QT syndrome in a family (internal data). Taken together, this variant is interpreted as likely pathogenic.

Long QT syndrome;C0235480:Paroxysmal atrial fibrillation Pathogenic:1

Dec 05, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Specific KCNQ1 criteria: PS4_moderat, PM2, PM4_supporting, PP1

Long QT syndrome Uncertain:1

Sep 13, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant identified in the KCNQ1 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNQ1-topology. It is unclear how this variant impacts the function of this protein. This variant has been reported to segregate with long QT syndrome (LQTS) in a family and has also been reported in an independent individual that was referred for LQTS genetic testing (PMID: 14731347, 23098067). ClinVar contains an entry for this variant (Variation ID: 52947). This variant is not present in population databases (ExAC no frequency). This variant, c.1066_1071delCAGCAG, results in the deletion of 2 amino acid(s) of the KCNQ1 protein (p.Gln356_Gln357del), but otherwise preserves the integrity of the reading frame.

Long QT syndrome 1 Other:1

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=4/196	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397508073; hg19: chr11-2606473;