11-2585225-C-G

Variant names:

• chr11-2585225-C-G
• rs199472765
• NM_000218.3:c.1046C>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1046C>G​(p.Ser349Trp) 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. 13/23 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. S349P) has been classified as Likely 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:5 O:1
• Conservation: PhyloP100: 7.39
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr11-2585224-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52941.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-2585225-C-G is Pathogenic according to our data. Variant chr11-2585225-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1046C>G	p.Ser349Trp	missense_variant	Exon 8 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1046C>G	p.Ser349Trp	missense_variant	Exon 8 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 14, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The S349W mutation was first identified in one individual diagnosed with LQTS (Splawski I et al., 2000) and subsequently identified in 15 individuals from 3 families enrolled in the International LQTS Registry (Horr S et al., 2011). The individuals from this registry who harbored the S349W mutation appeared to experience more cardiac events than individuals who harbored other haploinsufficient mutations, despite having a normal ECG during baseline examination. In vitro functional studies showed S349W had a relatively mild effect on the ion channel current but a pronounced effect on channel activation (Horr S et al., 2011). S349W was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. S349W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Missense mutations in this same residue (S349P) and in nearby residues (G345R, G345E, G345V, G350R, G350V, F351S) have been reported in association with LQTS, supporting the functional importance of this region of the protein. The variant is found in KCNQ1 panel(s).

Jul 28, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PM2, PS3_supporting, PS4_moderate

Long QT syndrome Pathogenic:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 349 of the KCNQ1 protein (p.Ser349Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 20662986, 22539601; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 52942). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 20662986). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Cardiovascular phenotype Pathogenic:1

Feb 07, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S349W variant (also known as c.1046C>G), located in coding exon 8 of the KCNQ1 gene, results from a C to G substitution at nucleotide position 1046. The serine at codon 349 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals from long QT syndrome cohorts (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Gemma LW et al. J Cardiovasc Electrophysiol, 2011 Oct;22:1141-6; Jons C et al. Sci Transl Med, 2011 Mar;3:76ra28; Stattin EL et al. BMC Cardiovasc Disord, 2012 Oct;12:95). It has also been identified likely in trans with a KCNQ1 pathogenic variant in an individual diagnosed with Jervell and Lange-Nielsen syndrome (Winbo A et al. Europace, 2012 Dec;14:1799-806). Functional studies suggest this variant may result in deficient protein function (Horr S et al. J Cardiovasc Electrophysiol, 2011 Feb;22:193-200). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Congenital long QT syndrome 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 as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:11668638;PMID:14678125;PMID:15840476;PMID:20662986;PMID:17999538;PMID:17470695;PMID:22539601). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;.
PhyloP100		7.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.94
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.97
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199472765; hg19: chr11-2606455;