11-2847808-G-A

Position:

• chr11-2847808-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000218.3(KCNQ1):​c.1836G>A​(p.Met612Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000423 in 1,417,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.43

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Interaction with AKAP9 (size 28) in uniprot entity KCNQ1_HUMAN there are 38 pathogenic changes around while only 1 benign (97%) in NM_000218.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1836G>A	p.Met612Ile	missense_variant	16/16	ENST00000155840.12
KCNQ1-AS1	NR_130721.1	n.778-7366C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1836G>A	p.Met612Ile	missense_variant	16/16	1	NM_000218.3	P1
KCNQ1-AS1	ENST00000440887.2	n.777-7366C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000423 AC: 6 AN: 1417832 Hom.: 0 Cov.: 31 AF XY: 0.00000428 AC XY: 3 AN XY: 701322

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: 0.00

Gnomad4 NFE exome AF: 0.00000551

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 29, 2016

This sequence change replaces methionine with isoleucine at codon 612 of the KCNQ1 protein (p.Met612Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNQ1-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Uncertain	0.63	D;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	0.71	N;.;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.56	N;N;.
REVEL	Uncertain	0.61
Sift	Benign	0.69	T;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0090	B;.;.
Vest4		0.33
MutPred		0.67		Gain of catalytic residue at L617 (P = 0.052);.;.;
MVP		0.92
MPC		0.42
ClinPred		0.29	T
GERP RS		2.9
Varity_R		0.17
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs878853756; hg19: chr11-2869038;