rs199472931

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000238.4(KCNH2):​c.1781G>A​(p.Gly594Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Consequence

KCNH2
NM_000238.4 missense

Scores

11
5
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1O:1

Conservation

PhyloP100: 7.79
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
Variant 7-150951612-C-T is Pathogenic according to our data. Variant chr7-150951612-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67271.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.1781G>A p.Gly594Asp missense_variant 7/15 ENST00000262186.10 NP_000229.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.1781G>A p.Gly594Asp missense_variant 7/151 NM_000238.4 ENSP00000262186 P1Q12809-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152256
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
34
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152256
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Long QT syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 31, 2019In 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. This variant has been reported to affect KCNH2 protein function (PMID: 25417810). This variant has been observed in several individuals clinical features of long QT syndrome (LQTS) (PMID: 22949429, 17905336, 19716085, 23098067, 23158531). ClinVar contains an entry for this variant (Variation ID: 67271). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 594 of the KCNH2 protein (p.Gly594Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 03, 2022The c.1781G>A (p.G594D) alteration is located in exon 7 (coding exon 7) of the KCNH2 gene. This alteration results from a G to A substitution at nucleotide position 1781, causing the glycine (G) at amino acid position 594 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Congenital long QT syndrome Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
.;D;D
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.9
.;L;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.6
D;D;.
REVEL
Pathogenic
0.88
Sift
Uncertain
0.014
D;D;.
Sift4G
Benign
0.15
T;T;T
Polyphen
0.43
B;D;.
Vest4
0.92
MutPred
0.86
.;Gain of loop (P = 0.0435);.;
MVP
0.99
MPC
2.5
ClinPred
0.99
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.56
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199472931; hg19: chr7-150648700; COSMIC: COSV51126350; API