rs397508073

chr11-2585243-TGCAGCA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_000218.3(KCNQ1):c.1066_1071del(p.Gln356_Gln357del) variant causes a 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). Synonymous variant affecting the same amino acid position (i.e. V355V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 8.70

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 id is 52947.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr11-2585243-TGCAGCA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1066_1071del	p.Gln356_Gln357del	inframe_deletion	8/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1066_1071del	p.Gln356_Gln357del	inframe_deletion	8/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.685_690del	p.Gln229_Gln230del	inframe_deletion	8/16	1
KCNQ1	ENST00000496887.7	c.771+1700_771+1705del		intron_variant		5
KCNQ1	ENST00000646564.2	c.588+1700_588+1705del		intron_variant

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:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

KCNQ1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2023

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 (Alamut Visual Plus v1.6.1). However, such prediction programs are imperfect and cannot substitute for mRNA studies. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 13, 2019

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

not provided, no classification provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508073; hg19: chr11-2606473;