11-2572979-G-C

Position:

• chr11-2572979-G-C

Variant summary

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

The ENST00000155840.12(KCNQ1):​c.914G>C​(p.Trp305Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W305L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 ENST00000155840.12 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• 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 hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000155840.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2572980-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2837284.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 11-2572979-G-C is Pathogenic according to our data. Variant chr11-2572979-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572979-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.914G>C	p.Trp305Ser	missense_variant	6/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.914G>C	p.Trp305Ser	missense_variant	6/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.533G>C	p.Trp178Ser	missense_variant	6/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.653G>C	p.Trp218Ser	missense_variant	7/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-10456G>C		intron_variant				ENSP00000495806

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: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460482 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Jervell and Lange-Nielsen syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1998

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2023

Identified in patients with LQTS and JLNS referred for genetic testing at GeneDx and in published literature (PMID: 9020846, 9781056, 15840476, 19490272, 19716085, 22456477, 23158531); Observed in homozygous state in a patient in published literature with JLNS and not observed in homozygous state in controls (PMID: 9781056, 9020846); Published functional studies demonstrate a damaging effect as the W305S variant results in decreased potassium channel current (PMID: 9312006); 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; This variant is associated with the following publications: (PMID: 19716085, 26344792, 9781056, 34505893, 10973849, 17999538, 15840476, 19490272, 23158531, 21451124, 22456477, 26669661, 32383558, 34076677, 9020846, 9312006) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 30, 2022

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 305 of the KCNQ1 protein (p.Trp305Ser). This variant is present in population databases (rs120074186, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of long QT syndrome and Jervell and Lange-Nielsen syndrome (PMID: 9781056, 15840476, 19490272, 19716085, 21451124, 22456477, 23139254). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3127). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9312006, 10090886, 21451124, 26344792). This variant disrupts the p.Trp305 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 22949429, 26344792), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2022

The p.W305S variant (also known as c.914G>C), located in coding exon 6 of the KCNQ1 gene, results from a G to C substitution at nucleotide position 914. The tryptophan at codon 305 is replaced by serine, an amino acid with highly dissimilar properties, and is located in the pore region of the protein. This variant has been reported in individuals and families with long QT syndrome (LQTS), as well as in LQTS clinical genetic testing cohorts; however, individual clinical details were limited (Tester DJ et al. Heart Rhythm, 2005;2:507-17; Jons C et al. Sci Transl Med, 2011 Mar;3:76ra28; Itoh H et al. Eur J Hum Genet, 2016 08;24:1160-6). This alteration was also detected in three homozygous cases, including two siblings and an unrelated proband, with autosomal recessive Jervell and Lange-Nielsen syndrome (Neyroud N et al. Eur. J. Hum. Genet. 1998;6:129-33). In vitro functional analyses suggest that this variant significantly reduces potassium current, although in one study the impact was lessened when the alteration was co-expressed with wildtype KCNQ1 (Chouabe C et al. EMBO J. 1997;16:5472-9; Jons C et al. Sci Transl Med. 2011;3:76ra28). Internal structural analysis indicates that this alteration is moderately disruptive in a sensitive region and more disruptive than a nearby known pathogenic variant (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

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

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9781056;PMID:15840476;PMID:19716085;PMID:9312006;PMID:17999538). 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	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-14	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		1.0
MutPred		0.95		Gain of glycosylation at W305 (P = 0.0053);.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		3.9
Varity_R		1.0
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;