7-150974775-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The ENST00000262186.10(KCNH2):ā€‹c.243G>Cā€‹(p.Gln81His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,142 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 Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q81E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

KCNH2
ENST00000262186.10 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 2.54
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000262186.10
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.243G>C p.Gln81His missense_variant 2/15 ENST00000262186.10 NP_000229.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.243G>C p.Gln81His missense_variant 2/151 NM_000238.4 ENSP00000262186 P1Q12809-1
KCNH2ENST00000532957.5 linkuse as main transcriptn.466G>C non_coding_transcript_exon_variant 2/92

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1454142
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
722974
show subpopulations
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:
0.0000192
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Long QT syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteSep 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with long QT syndrome 2 (MIM#613688). Gain of function is also a known mechanism associated with short QT syndrome 1 (MIM#609620) (OMIM, PMIDs: 10753933, 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated PAS 9 domain (DECIPHER). (I) 0704 - Other missense variants comparable to the one identified in this case have limited previous evidence for pathogenicity. p.(Gln81Pro) and p.(Gln81Arg) have been reported in individuals with a diagnosis of LQTS and suspected LQTS, respectively (PMIDs: 34546463, 27041096). In addition, p.(Gln81Lys) has been reported as a VUS in an individual with epilepsy (PMID: 31696929). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported as a VUS by two clinical testing laboratories, including in an individual with LQTS, three individuals with possible LQTS and one unaffected individual (ClinVar, personal communication). It has also been reported in a child who died in her sleep at 21 months old who had a clinical history of febrile convulsions, and in her asymptomatic father (PMID: 20167303). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Long QT syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRoyal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory HubSep 08, 2017This variant has not been detected in control populations (ExAC), and has been reported once in the literature, in a 21 month old who died suddenly, it was also detected in the healthy father (Gladding et al 2010 Heart Rhythm 7(4):481-6) . The variant is located in the N-terminus region, which is a hotspot for mutations. The affecte amino acid is highly conserved, how in silico tools offer conflicting evidence as to the damaging effect on protein function -
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 04, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67399). This missense change has been observed in individual(s) with sudden death after a history of febrile convulsions (PMID: 20167303). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 81 of the KCNH2 protein (p.Gln81His). -
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:20167303). 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
Uncertain
0.54
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.87
D;D
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.21
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.85
T;D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
0.97
D;D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-2.8
D;.
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0040
D;.
Sift4G
Uncertain
0.015
D;D
Polyphen
0.45
B;.
Vest4
0.64
MutPred
0.38
Loss of MoRF binding (P = 0.1576);.;
MVP
0.94
MPC
1.9
ClinPred
0.95
D
GERP RS
1.6
Varity_R
0.87
gMVP
0.95

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

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

Other links and lift over

dbSNP: rs199472849; hg19: chr7-150671863; COSMIC: COSV51229745; API