rs794728481

chr7-150951709-G-Achr7-150951709-G-T

Variant summary

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

The NM_000238.4(KCNH2):c.1684C>T(p.His562Tyr) 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. 13/21 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. H562R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.92

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150951708-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 7-150951709-G-A is Pathogenic according to our data. Variant chr7-150951709-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1684C>T	p.His562Tyr	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1684C>T	p.His562Tyr	missense_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2012

The His562Tyr mutation in the KCNH2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. His562Tyr results in a non-conservative amino acid substitution of a positively charged Histidine with a neutral, polar Tyrosine. Located in the S5 segment of the KCNH2 gene, different mutations at the same codon (His562Arg, His562Pro) as well as mutations in nearby codons (Ala561Pro, Ala561Thr, Ala561Val, Trp563Cys, Trp563Gly) have been reported in association with LQTS, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports His562Tyr was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, the presence of His562Tyr in the KCNH2 gene is consistent with an autosomal dominant form of LQTS. The variant is found in LQT panel(s). -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2022

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. This variant disrupts the p.His562 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15242738, 16432067, 22949429, 25417810, 25819988). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 200733). This missense change has been observed in individuals with long QT syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 562 of the KCNH2 protein (p.His562Tyr). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2017

The p.H562Y variant (also known as c.1684C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1684. The histidine at codon 562 is replaced by tyrosine, an amino acid with similar properties. Based on internal structural analysis, this variant, which is located within the S5 transmembrane segment of the KCNH2 protein, interacts with an adjacent monomer and is comparably stabilizing relative to a known pathogenic alteration at the same position, suggesting an impact on the membrane interface (Long SB et al. Nature. 2007;450:376-82; Liu J et al. J Gen Physiol. 2002;120:723-37). This variant has not been described in the literature to date; however, other alterations involving the same amino acid, p.H562R (c.1685A>G) and p.H562P (c.1685A>C), have been reported in families with long QT syndrome (LQTS) and have demonstrated deficient protein trafficking or reduced current by functional in vitro analyses of the potassium channel (Sharma D et al. J Mol Cell Cardiol. 2004;37:79-89; Anderson CL et al. Circulation. 2006;113:365-73; Anderson CL et al. Nat Commun. 2014;5:5535; Muñoz-Esparza C et al. Rev Esp Cardiol (Engl Ed). 2015;68:861-8). This amino acid position is highly conserved in available vertebrate species. In addition, p.H562Y is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.79		.;Loss of stability (P = 0.3675);.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		1.0

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: rs794728481; hg19: chr7-150648797;