11-2445299-GGCCGCGCCC-GGCCGCGCCCGCCGCGCCC

Variant names:

• chr11-2445299-G-GGCCGCGCCC
• rs397508107
• NM_000218.3:c.211_219dupGCCGCGCCC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_000218.3(KCNQ1):​c.211_219dupGCCGCGCCC​(p.Ala71_Pro73dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000283 in 1,415,278 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 0.0720

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 Uncertain_significance. Variant got 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000218.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.211_219dupGCCGCGCCC	p.Ala71_Pro73dup	conservative_inframe_insertion	Exon 1 of 16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.211_219dupGCCGCGCCC	p.Ala71_Pro73dup	conservative_inframe_insertion	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1	c.211_219dupGCCGCGCCC	p.Ala71_Pro73dup	conservative_inframe_insertion	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1	c.-152_-144dupGCCGCGCCC		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.211_219dupGCCGCGCCC	p.Ala71_Pro73dup	conservative_inframe_insertion	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000646564.2	c.211_219dupGCCGCGCCC	p.Ala71_Pro73dup	conservative_inframe_insertion	Exon 1 of 11			ENSP00000495806.2
KCNQ1	ENST00000496887.7	c.24-74_24-66dupGCCGCGCCC		intron_variant	Intron 1 of 15	5		ENSP00000434560.2
KCNQ1	ENST00000345015.4	n.-23_-22insGCCGCGCCC		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150612 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000293 AC: 37 AN: 1264666 Hom.: 0 Cov.: 31 AF XY: 0.0000290 AC XY: 18 AN XY: 621672

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000339

Gnomad4 NFE exome AF: 0.0000353

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150612 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73524

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000444

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 29, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNQ1 c.211_219dupGCCGCGCCC (p.Ala71_Pro73dup) results in an in-frame duplication that is predicted to duplicate three amino acids (Ala-Ala-Pro) into the repeat region of encoded protein. The variant allele was found at a frequency of 1.9e-05 in 103628 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.211_219dupGCCGCGCCC in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Uncertain:1

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.211_219dup, results in the insertion of 3 amino acid(s) of the KCNQ1 protein (p.Ala71_Pro73dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397508107, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 53030). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Cardiovascular phenotype Uncertain:1

Jun 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211_219dupGCCGCGCCC (p.A71_P73dup) alteration is located in exon 1 (coding exon 1) of the KCNQ1 gene. The alteration consists of an in-frame duplication of 9 nucleotides from position 211 to 219, resulting in the duplication of 3 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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 v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508107; hg19: chr11-2466529;