11-2583459-G-T

Position:

• chr11-2583459-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.946G>T​(p.Gly316Trp) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G316E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.36

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 18 ACMG points.

• PM1: In a intramembrane_region Pore-forming; Name=Segment H5 (size 20) in uniprot entity KCNQ1_HUMAN there are 54 pathogenic changes around while only 0 benign (100%) 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 chr11-2583460-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-2583459-G-T is Pathogenic according to our data. Variant chr11-2583459-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583459-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.946G>T	p.Gly316Trp	missense_variant	7/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.946G>T	p.Gly316Trp	missense_variant	7/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.565G>T	p.Gly189Trp	missense_variant	7/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.685G>T	p.Gly229Trp	missense_variant	8/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.502G>T	p.Gly168Trp	missense_variant	3/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2013

p.Gly316Trp (GGG>TGG): c.946 G>T in exon 7 of the KCNQ1 gene (NM_000218.2). While the Gly316Trp mutation in the KCNQ1 gene has not been reported to our knowledge, other mutations affecting this same residue, Gly316Val, Gly316Glu, and Gly316Arg, have been reported in association with LQTS. Additionally, mutations in neighboring residues (Tyr315Asn, Tyr315Cys, Asp317Asn, Asp317Tyr) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein. The Gly316Trp variant is a conservative amino substitution as these residues share similar properties, and are least likely to impact secondary structure. However, the Gly316 residue is conserved across species. In silico analysis predicts Gly316Trp is probably damaging to the protein structure/function. Furthermore, Gly316Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Gly316Trp in the KCNQ1 gene is interpreted as a likely disease-causing mutation. The variant is found in LQT panel(s). -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly316 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19808498, 20981542). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. ClinVar contains an entry for this variant (Variation ID: 200826). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 31737537). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 316 of the KCNQ1 protein (p.Gly316Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.90		Gain of sheet (P = 0.0477);.;.;
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.95
gMVP		1.0

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: rs104894255; hg19: chr11-2604689;