11-2572870-G-C

Position:

• chr11-2572870-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000218.3(KCNQ1):​c.805G>C​(p.Gly269Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G269D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.42

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2572871-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 11-2572870-G-C is Pathogenic according to our data. Variant chr11-2572870-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 200898.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-2572870-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.805G>C	p.Gly269Arg	missense_variant	6/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.805G>C	p.Gly269Arg	missense_variant	6/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.424G>C	p.Gly142Arg	missense_variant	6/16	1
KCNQ1	ENST00000496887.7	c.544G>C	p.Gly182Arg	missense_variant	7/16	5
KCNQ1	ENST00000646564.2	c.478-10565G>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2011

This missense change is denoted Gly269Arg (aka G269R) at the protein level and c.805 G>C at the cDNA level. Although the Gly269Arg mutation in the KCNQ1 gene has not been reported previously, two different mutations at the same position (Gly269Ser, Gly269Asp) have been reported multiple times in association with LQTS (Choi G et al, 2004, Wang Z et al., 2002, Tester et al., 2005, Chen S et al., 2003). In addition, mutations in nearby codons (Leu266Pro, Ile268Ser, Gly272Asp, Gly272Val) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein. Gly269Arg results in a non-conservative amino acid substitution of a non polar Glycine with a positively charged Arginine at a residue that is conserved across species. The NHLBI ESP Exome Variant Server reports Gly269Arg was not observed in at least 5,108 individuals from Caucasian and African American backgrounds. The variant is found in LQT panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.96, 0.95
MutPred		0.88		.;Gain of methylation at G269 (P = 0.0242);.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.99
gMVP		0.99

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: rs120074193; hg19: chr11-2594100;