rs199473397

Positions:

• chr11-2570701-A-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.551A>C​(p.Tyr184Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y184H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 ENST00000155840.12 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 8.58

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr11-2570700-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 11-2570701-A-C is Pathogenic according to our data. Variant chr11-2570701-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570701-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.551A>C	p.Tyr184Ser	missense_variant	3/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.551A>C	p.Tyr184Ser	missense_variant	3/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.170A>C	p.Tyr57Ser	missense_variant	3/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.290A>C	p.Tyr97Ser	missense_variant	4/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-12734A>C		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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 variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants 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) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated S2/S3 transmembrane segment within the ion transport domain (DECIPHER, PMID: 10973849). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Tyr184Asp) and p.(Tyr184His) variants have been reported in individuals with LQTS (ClinVar; PMIDs: 32893267, 19716085). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five individuals with LQTS (ClinVar; PMIDs: 10220144, 10973849, 21350584, 23963746). Additionally, it has been proposed as a Dutch founder variant (PMID: 21350584). (SP) 0906 - Segregation evidence for this variant is inconclusive. While this variant has been shown to segregate in five affected individuals within the same family, it was also identified in five other asymptomatic family members whose ages ranged from 9-44 years old (PMID: 10220144). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant protein co-expressed with WT protein in Xenopus oocytes resulted in channel current changes and channel rates of activation that were different from oocytes expressing just the WT protein and, were significantly different from oocytes mimicking the haploinsufficient phenotype. This variant demonstrated a partial dominant-negative mechanism (PMID: 21451124). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2017

The p.Y184S variant (also known as c.551A>C), located in coding exon 3 of the KCNQ1 gene, results from an A to C substitution at nucleotide position 551. The tyrosine at codon 184 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in several individuals with long QT syndrome (LQTS) (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Kapa S et al. Circulation, 2009 Nov;120:1752-60; Giudicessi JR et al. Circ Cardiovasc Genet, 2012 Oct;5:519-28). In one Dutch family, this alteration co-segregated with disease in five affected family members across three generations, as well as being detected in additional asymptomatic carriers with somewhat prolonged QT intervals and one carrier with a normal QT interval (Jongbloed RJ et al. Hum. Mutat., 1999;13:301-10). Limited functional studies have suggested this alteration causes a dominant negative effect in transfected cells (Jons C et al. Sci Transl Med, 2011 Mar;3:76ra28). Alternate amino acid substitutions at this position, including Y184H and Y184C, have also been reported in individuals with LQTS, but clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Gao Y et al. Cardiology, 2016 Oct;133:73-8).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

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:10220144;PMID:10973849;PMID:12566525;PMID:19841300;PMID:17470695). 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	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-8.4	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		1.0, 0.98
MutPred		0.95		.;Gain of disorder (P = 0.0493);.;
MVP		0.97
MPC		1.4
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.98

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: rs199473397; hg19: chr11-2591931;