rs796052195

Positions:

• chr7-150951544-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Strong

The NM_000238.4(KCNH2):​c.1849T>C​(p.Phe617Leu) 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 Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.38

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 12 ACMG points.

• PS1: Transcript NM_000238.4 (KCNH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 392690
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1849T>C	p.Phe617Leu	missense_variant	7/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1849T>C	p.Phe617Leu	missense_variant	7/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 06, 2019	This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Phe617 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 25987402), which suggests that this may be a clinically significant amino acid residue. 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 C0"). This variant has been observed in individuals affected with clinical features of long QT syndrome (PMID: 26132555, Invitae). ClinVar contains an entry for this variant (Variation ID: 207940). This sequence change replaces phenylalanine with leucine at codon 617 of the KCNH2 protein (p.Phe617Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. -
Likely pathogenic, no assertion criteria provided	research	Medical Research Institute, Tokyo Medical and Dental University	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	.;D;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;H;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	D;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;.
Sift4G	Benign	0.073	T;T;T
Polyphen		0.31	B;P;.
Vest4		0.99
MutPred		0.80		.;Loss of sheet (P = 0.1158);.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.93
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: rs796052195; hg19: chr7-150648632;