rs876661348

Variant names:

• chr7-150951588-A-G
• rs876661348
• NM_000238.4:c.1805T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP2 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). Synonymous variant affecting the same amino acid position (i.e. L602L) has been classified as Likely benign.

• 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 28 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• 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 VariationId is 234996.
• 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 rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1805T>C	p.Leu602Pro	missense_variant	Exon 7 of 15	ENST00000262186.10	NP_000229.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

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

Dec 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 31, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
CardioboostArm	Benign	0.000017
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;.
PhyloP100		0.64
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
Mutation Taster		=62/38	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs876661348; hg19: chr7-150648676;