chr7-150974775-C-G

Variant names:

• chr7-150974775-C-G
• rs199472849
• NM_000238.4:c.243G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000238.4(KCNH2):​c.243G>C​(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q81R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 2.54
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.243G>C	p.Gln81His	missense_variant	Exon 2 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.243G>C	p.Gln81His	missense_variant	Exon 2 of 15	1	NM_000238.4	ENSP00000262186.5

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

African (AFR) AF: 0.00 AC: 0 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 44226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39418

South Asian (SAS) AF: 0.00 AC: 0 AN: 85518

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 51988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5018

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108888

Other (OTH) AF: 0.00 AC: 0 AN: 59884

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 2 Uncertain:1

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based 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

Sep 08, 2017

Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Feb 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). In 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"). This missense change has been observed in individual(s) with sudden death after a history of febrile convulsions (PMID: 20167303). ClinVar contains an entry for this variant (Variation ID: 67399). -

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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
CardioboostArm	Benign	0.046
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;.
PhyloP100		2.5
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
Mutation Taster		=6/94	disease causing

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