7-150948452-G-T

Position:

• chr7-150948452-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000238.4(KCNH2):​c.2684C>A​(p.Thr895Lys) variant causes a missense change. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T895M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.77

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150948452-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67426.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=2, Uncertain_significance=7}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.2684C>A	p.Thr895Lys	missense_variant	11/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.2684C>A	p.Thr895Lys	missense_variant	11/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.1664C>A	p.Thr555Lys	missense_variant	7/11	1
KCNH2	ENST00000684241.1	n.3517C>A		non_coding_transcript_exon_variant	9/13

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1099876 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 550626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 10, 2023

This missense variant replaces threonine with lysine at codon 895 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2021

The p.T895K variant (also known as c.2684C>A), located in coding exon 11 of the KCNH2 gene, results from a C to A substitution at nucleotide position 2684. The threonine at codon 895 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 17, 2023

The c.2684C>A p.(Thr895Lys) variant in the KCNH2 gene has been deposited in ClinVar [ClinVar ID: 927873] as Variant of Uncertain Significance and, to our current knowledge, has not been reported in affected individuals in the literature. The c.2684C>A variant is observed in 3 alleles (~0.001 %minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.2684C>A variant in KCNH2 is located in exon 11 of this 15-exon gene, and predicted to replace an evolutionarily conserved threonine amino acid with lysine at position 895 in the second disordered region of the encoded protein [UniProtKB ID: Q12809]. In silico predictions are moderately in favor of damaging effect for the p.(Thr895Lys) variant (CADD v1.6 = 21.5, REVEL = 0.662); however, there are no functional studies to support or refute these predictions. Based on available evidence this c.2684C>A p.(Thr895Lys) variant identified in KCNH2 is classified as a Variant of Uncertain Significance. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 28, 2023

This missense variant replaces threonine with lysine at codon 895 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.043
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.4	.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.89	T;T
Sift4G	Benign	0.99	T;T
Polyphen		0.46	P;P
Vest4		0.58
MutPred		0.41		.;Loss of phosphorylation at T895 (P = 6e-04);
MVP		0.99
MPC		0.42
ClinPred		0.93	D
GERP RS		3.9
Varity_R		0.22
gMVP		0.83

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: rs199473434; hg19: chr7-150645540;