rs199472999

Positions:

• chr7-150949034-A-C
• chr7-150949034-A-G

Variant summary

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

The ENST00000262186.10(KCNH2):​c.2414T>G​(p.Phe805Cys) 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. 12/21 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. F805S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH2 ENST00000262186.10 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.32

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000262186.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150949034-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 67396.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 7-150949034-A-C is Pathogenic according to our data. Variant chr7-150949034-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150949034-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2414T>G	p.Phe805Cys	missense_variant	10/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2414T>G	p.Phe805Cys	missense_variant	10/15	1	NM_000238.4	ENSP00000262186	P1
KCNH2	ENST00000330883.9	c.1394T>G	p.Phe465Cys	missense_variant	6/11	1		ENSP00000328531
KCNH2	ENST00000684241.1	n.3247T>G		non_coding_transcript_exon_variant	8/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 16, 2013

p.Phe805Cys (TTT>TGT): c.2414 T>G in exon 10 of the KCNH2 gene (NM_000238.2)The Phe805Cys mutation in the KCNH2 gene has been reported previously in one individual diagnosed with LQTS (Splawski I et al., 2000). Functional studies have shown that Phe805Cys results in a trafficking defect and consequent reduced potassium channel current (Ficker E et al., 2002; Anderson C et al., 2006). Also, a mutation affecting this same residue, Phe805Ser, has been reported in association with LQTS and was absent from more than 400 control alleles in this study (Splawski I et al., 2000). Mutations in nearby residues (Gly800Glu, Gly800Trp, Gly806Glu) have been reported in association with LQTS, supporting the functional importance of this residue and this region of the protein. Furthermore, Phe805Cys 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. In summary, Phe805Cys in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). -

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2016

For these reasons, this variant has been classified as Likely Pathogenic. This variant identified in the KCNH2 gene is located in the cytoplasmic cyclic nucleotide binding region of the resulting protein (PMID: 19841300). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. Experimental studies have shown that this variant affects protein trafficking and therefore potassium channel current (PMID: 16432067, 23303164, 11741928, 12837749) This variant has been reported in a family affected with long QT syndrome (PMID: 11854117). ClinVar contains an entry for this variant (Variation ID: 67397). This variant is not present in population databases (rs199472999, ExAC no frequency). This sequence change replaces phenylalanine with cysteine at codon 805 of the KCNH2 protein (p.Phe805Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2017

The p.F805C variant (also known as c.2414T>G), located in coding exon 10 of the KCNH2 gene, results from a T to G substitution at nucleotide position 2414. The phenylalanine at codon 805 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cyclic nucleotide binding domain. This alteration has been previously reported in long QT syndrome cohorts; however, clinical details were limited (Splawski I et al. Circulation. 2000;102:1178-85; Tester DJ et al. Heart Rhythm. 2005;2:507-17). In vitro analyses performed in human cell lines by multiple labs demonstrate that F805C results in defective trafficking and reduced potassium current (Ficker E et al. J. Biol. Chem. 2002;277:4989-98; Delisle BP et al. J. Biol. Chem. 2003;278:35749-54; Walker VE et al. J. Biol. Chem. 2007;282:23509-16). A functional assay in zebrafish also suggests that this variant results in deficient protein function (Jou CJ et al. Circ. Res. 2013;112:826-30). Internal structural analysis indicates that the alteration lies buried in a domain and is more destabilizing than other variants in the region; however, the only other buried variant in the region is stabilizing (Wang W and McKinnon R. Cell. 2017;169(3):422-430). 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:10973849;PMID:11854117;PMID:15840476;PMID:16432067;PMID:18468596;PMID:11741928). 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	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.94		.;Gain of sheet (P = 0.0827);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
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: rs199472999; hg19: chr7-150646122;