11-2572979-G-T

Variant names:

• chr11-2572979-G-T
• rs120074186
• NM_000218.3:c.914G>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000218.3(KCNQ1):​c.914G>T​(p.Trp305Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W305R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U: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 11 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 chr11-2572978-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-2572979-G-T is Pathogenic according to our data. Variant chr11-2572979-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200824.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_pathogenic=3}. Variant chr11-2572979-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.914G>T	p.Trp305Leu	missense_variant	Exon 6 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.914G>T	p.Trp305Leu	missense_variant	Exon 6 of 16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.533G>T	p.Trp178Leu	missense_variant	Exon 6 of 16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.653G>T	p.Trp218Leu	missense_variant	Exon 7 of 16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-10456G>T		intron_variant	Intron 2 of 10			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249180 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460482 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726452

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 1 Pathogenic:3

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function mutations result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function mutations can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 20301308, OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to leucine (exon 6). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. The variant is located in the P-loop region of the KCNQ1 gene (PMID: 26344792). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. The p.W305S, p.W305R and p.W305C comparable variants have been described in multiple individuals with LQTS or JLNS (PMIDs: 1584047; 9781056; 23158531; 22456477). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in four unrelated individuals with LQTS (ClinVar; PMIDs: 26344792; 28532774). (P) 1002 - Limited functional evidence supporting abnormal protein function. Using whole-cell patch clamp technique, the p.W305L mutant cDNA transfected into COS-7 monkey kidney cells demonstrated reduced Kv7.1 channel peak current density compared to COS-7 cells transfected with WT cDNA. However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification (PMID: 26344792). (N) 1208 - Inherited information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Apr 20, 2018

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Pathogenic:1 Uncertain:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 305 of the KCNQ1 protein (p.Trp305Leu). This variant is present in population databases (rs120074186, gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 26344792). ClinVar contains an entry for this variant (Variation ID: 200824). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 26344792). This variant disrupts the p.Trp305 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19490272, 19716085, 21451124, 26344792). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tryptophan with leucine at codon 305 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved pore region (a.a. 300-320). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant results in significantly decreased peak current densities compared to wild type protein (PMID: 26344792). This variant has been reported in 2 individuals affected with long QT syndrome (PMID: 26344792, 28532774) and 2 individuals with suspected long QT syndrome (PMID: 31737537). This variant was found to partially segregate in a family with long QT syndrome and a syncope phenotype (PMID: 26344792). A different missense variant occurring at the same codon, p.Trp305Ser, is known to be disease-causing (ClinVar variation ID: 3127). This variant has been identified in 1/249180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this p.Trp305Leu variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jervell and Lange-Nielsen syndrome 1 Pathogenic:1

Jan 03, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000200824, PMID:26344792, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26344792, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003127, PMID:9781056,19716085, PM5_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3CNET: 0.999, PP3_P). A missense variant is a common mechanism associated with Jervell and Lange-Nielsen syndrome (PP2_P).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Aug 16, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect of the potassium ion channel function, with reduced peak current density in transfected COS7 cells (Zhou et al., 2015); This variant is associated with the following publications: (PMID: 26344792, 28532774, 31737537, 32431610, 34428338) -

Cardiovascular phenotype Uncertain:1

Jan 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W305L variant (also known as c.914G>T), located in coding exon 6 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 914. The tryptophan at codon 305 is replaced by leucine, an amino acid with similar properties. This variant has been detected in an individual with long QT syndrome (LQTS) and in relatives with normal QTc intervals (Zhou H et al. Cardiol Young, 2016 Apr;26:754-63). This variant was also detected in an individual with prolonged QTc in the setting of congenital heart disease, and in individuals referred for LQTS genetic testing for whom clinical details were limited (Ebrahim MA et al. Am. J. Cardiol., 2017 Jul;120:256-261; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This variant was also detected in a genome sequencing cohort in individuals with normal ECGs or who were not indicated as having LQTS on ECG (Elfatih A et al. Hum Mutat, 2021 Aug). In one in vitro study, this variant resulted in reduced current density compared to wild type when expressed in the mock-homozygous state (Zhou H et al. Cardiol Young, 2016 Apr;26:754-63). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-13	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.86		Loss of helix (P = 0.0376);.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs120074186; hg19: chr11-2594209;