dbSNP rs199472680: KCNQ1:p.Gly119Asp (chr11-2445454-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000218.3(KCNQ1):c.356G>A(p.Gly119Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G119V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 6.87

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2445453-GGC-GTT is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.356G>A	p.Gly119Asp	missense_variant	Exon 1 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9
KCNQ1	NM_001406836.1 link	c.356G>A	p.Gly119Asp	missense_variant	Exon 1 of 15		NP_001393765.1
KCNQ1	NM_001406838.1 link	c.356G>A	p.Gly119Asp	missense_variant	Exon 1 of 11		NP_001393767.1
KCNQ1	NM_001406837.1 link	c.-7G>A		5_prime_UTR_variant	Exon 1 of 17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.356G>A	p.Gly119Asp	missense_variant	Exon 1 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000345015.4 link	n.133G>A		non_coding_transcript_exon_variant	Exon 1 of 3	1
KCNQ1	ENST00000496887.7 link	c.95G>A	p.Gly32Asp	missense_variant	Exon 2 of 16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.356G>A	p.Gly119Asp	missense_variant	Exon 1 of 11			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1444578

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718944

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported in the following publications (PMID:16487223). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.6

.;L;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.1

D;D;.

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

0.79

.;P;.

Vest4

0.74

MutPred

0.77

.;Gain of ubiquitination at K121 (P = 0.0704);.;

MVP

0.97

MPC

1.7

ClinPred

0.99

GERP RS

3.2

Varity_R

0.94

gMVP

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over