rs876661348

Positions:

• chr7-150951588-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_000238.4(KCNH2):​c.1805T>C​(p.Leu602Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 0.640

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]

KCNH2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Extracellular (size 42) in uniprot entity KCNH2_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-150951588-A-G is Pathogenic according to our data. Variant chr7-150951588-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234996.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27121696). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1805T>C	p.Leu602Pro	missense_variant	7/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1805T>C	p.Leu602Pro	missense_variant	7/15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 602 of the KCNH2 protein (p.Leu602Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 26066609; Invitae). ClinVar contains an entry for this variant (Variation ID: 234996). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Dec 31, 2013

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Leu602Pro Based on the evidence reviewed below, we classify this variant as a variant of uncertain significance (VUS). The Leu602Pro variant in the KCNH2 gene is novel, and has not been previously reported as a disease-causing mutation nor as a benign polymorphism to our knowledge (after searches of PubMed and Google). Variation at several nearby residues has been associated with LQT2: I593R, I593T, I593G, I593X, P596L, P596R, G601S, G604S, D609N, D609H, D609G, Y611H, Y611X, V612L (UniProtKB; IRCCS Fondazione Salvatore Maugeri database). This is a conservative amino acid change, resulting in the replacement of a nonpolar leucine with a nonpolar proline. The leucine at this location varies in 9 of 32 mammalian species sequenced, and proline is the normal amino acid in stickleback fish. The adjacent residues similarly vary across species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign”. In total the variant has not been seen in >5330 individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals. There is no variation at this codon listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm), as of May 13, 2012. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2024

Identified in patient with LQTS referred for genetic testing at GeneDx and in published literature (PMID: 26066609); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19841300, 36480497, 26066609) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The p.L602P variant (also known as c.1805T>C), located in coding exon 7 of the KCNH2 gene, results from a T to C substitution at nucleotide position 1805. The leucine at codon 602 is replaced by proline, an amino acid with similar properties, and is located in the transmembrane-spanning S5/pore region. This alteration has been detected in an individual reported to have QT syndrome (LQTS); however, clinical details were limited (Steffensen AB et al. Sci Rep. 2015;5:10009). This amino acid position is not well conserved in available vertebrate species, and proline is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.67	.;D;D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.76	T;T;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.035	.;N;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.35	N;N;.
REVEL	Uncertain	0.44
Sift	Benign	0.24	T;T;.
Sift4G	Benign	0.21	T;T;T
Polyphen		0.029	B;B;.
Vest4		0.24
MutPred		0.53		.;Loss of stability (P = 0.0115);.;
MVP		0.77
MPC		1.5
ClinPred		0.087	T
GERP RS		2.9
Varity_R		0.17
gMVP		0.96

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: rs876661348; hg19: chr7-150648676;