11-2768894-A-C

Position:

• chr11-2768894-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1565A>C​(p.Tyr522Ser) variant causes a missense change. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.03

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 11-2768894-A-C is Pathogenic according to our data. Variant chr11-2768894-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2768894-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.1565A>C	p.Tyr522Ser	missense_variant	12/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1565A>C	p.Tyr522Ser	missense_variant	12/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.1184A>C	p.Tyr395Ser	missense_variant	12/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.1208A>C	p.Tyr403Ser	missense_variant	12/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.1025A>C	p.Tyr342Ser	missense_variant	7/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 19, 2016	p.Tyr522Ser (Y522S; c.1565A>C) in the KCNQ1 gene (NM_000218.2) We have seen this variant in one family with clinically-confirmed long QT syndrome (LQTS). Proband testing was done at Familion, and was sent by providers at UCSF. The variant has been shown to segregate with disease in at least 5 affected members of this family. This variant has been reported in just one individual in the literature, in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). We believe this individual to be the proband in the family we care for, so not an unrelated individual. There is strong published segregation data for our patients' family (Steffensen et al. 2015). Dr. Robert Nussbaum at UCSF collaborated with a Danish group to do in vitro functional characterization of the altered protein and found it to have loss of function. The authors show immunohistochemical data suggesting this is largely due to failure of the protein to be trafficked to the cell membrane from the endoplasmic reticulum (ER). What’s more, it is adjacent to another variant, p.Met520Arg, that has been shown to cause retention of the protein in the ER (Schmitt et al. 2007). They also report in the paper that the variant segregated with disease in 5 (possibly 6 if a drowning death is included) affected individuals. This is a conservative amino acid change, resulting in the replacement of a neutral, polar Tyrosine with a neutral, polar Serine. Tyrosine at this location is highly conserved across vertebrate species. Variation at nearby residues has been associated with LQTS, which may support the functional importance of this region of the protein: Thr513Ser, Ile514Thr, Ile517Thr, Arg518Gln, Arg518Gly, Arg518Pro, Arg519Cys, Met520Arg, Val524Gly, Ala525Thr, Ala525Val, Lys526Glu (HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 predicts the variant to be “Possibly Damaging” with a score of 0.771. The residue is not conserved across paralogs (http://cardiodb.org/Paralogue_Annotation/gene.php?name=KCNQ1). When Kapa et al. (2009) compared 388 “clinically definite” LQTS probands to ~1300 healthy controls, they found that while controls do have variants in all regions of the protein, LQTS cases were much more likely to have missense variants in the C-terminal cytoplasmic region of the KCNQ1 protein (amino acid residues 349-676), the pore region, transmembrane region, or linker region (residues 122-348)—rather than in the N-terminal domain (residues 1-121). Residue 522 is in the cytoplasmic domain of the protein, in which missense variants are 22x more frequent in LQTS cases than in controls (Kapa et al. 2009). It is in a region of the protein shown to interact with calmodulin (Schmitt et al. 2007). In total the variant has not been seen in >60,000 published controls and individuals from publicly available population datasets. The variant was not observed in 1300 published controls: (Kapplinger et al. 2009). Variation at this codon has not been seen in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this residue listed in 1000 Genomes as of 5/19/2016. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2012	p.Tyr522Ser (TAC>TCC):c.1565 A>C in exon 12 of the KCNQ1 gene (NM_000218.2). The Tyr522Ser mutation in the KCNQ1 gene has been reported previously in association with LQTS, and this mutation was absent from 2,600 control alleles (Kapplinger J et al., 2009). In addition, the NHLBI ESP Exome Variant Server reports Tyr522Ser was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Tyr522Ser results in a conservative substitution of one neutral, polar amino acid for another at a residue that is conserved across species. Mutations in nearby codons (Met520Arg, Val524Gly) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein. In summary, Tyr522Ser in the KCNQ1 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2017

The p.Y522S variant (also known as c.1565A>C), located in coding exon 12 of the KCNQ1 gene, results from an A to C substitution at nucleotide position 1565. The tyrosine at codon 522 is replaced by serine, an amino acid with dissimilar properties. This alteration segregated with disease in a family with long QT syndrome (LQTS) and functional studies by the same group suggested loss of function (Steffensen AB et al. Sci Rep, 2015 Jun;5:10009). This alteration was also reported in a study of LQTS clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). 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:19716085). 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
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.8	D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		0.77	P;.;D
Vest4		0.98
MutPred		0.87		Gain of disorder (P = 0.0181);.;.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.95
gMVP		0.99

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: rs199472789; hg19: chr11-2790124;