rs886039064

chr7-150947355-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000238.4(KCNH2):c.3125T>C(p.Leu1042Pro) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1042V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.24

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• PP5: Variant 7-150947355-A-G is Pathogenic according to our data. Variant chr7-150947355-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264155.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.3125T>C	p.Leu1042Pro	missense_variant	13/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3125T>C	p.Leu1042Pro	missense_variant	13/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2105T>C	p.Leu702Pro	missense_variant	9/11	1
KCNH2	ENST00000684241.1	n.3958T>C		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2016

The p.L1042P variant (also known as c.3125T>C) is located in coding exon 13 of the KCNH2 gene and results from a T to C substitution at nucleotide position 3125. The leucine at codon 1042 is replaced by proline, an amino acid with a few similar properties. This alteration was observed to segregate with long QT syndrome in one family tested by our laboratory. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5798 samples (11596 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Furthermore, structural analysis predicts that this alteration is likely to result in destabilization of a functional protein domain (PDB ID:4UZX, Jacobsen, J.O.B., Allen, M.D., Freund, S.M.V., Bycroft, M. High-Resolution NMR Structures of the Domains of Saccharomyces Cerevisiae Tho1 in press. can be obtained from http://www.rcsb.org/pdb/explore/explore.do?structureId=4UZX). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostArm	Benign	0.030
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.54		.;Loss of stability (P = 0.0065);
MVP		0.96
MPC		0.88
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.89

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: rs886039064; hg19: chr7-150644443;