rs199472880

Variant names:

• chr7-150958110-C-G
• rs199472880
• NM_000238.4:c.865G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-150958110-C-G
• chr7-150958110-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000238.4(KCNH2):​c.865G>C​(p.Glu289Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000262 in 1,144,896 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E289K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.69
• Publications: 9 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: Uncertain_significance. The variant received 3 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.865G>C	p.Glu289Gln	missense_variant	Exon 4 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.865G>C	p.Glu289Gln	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000262 AC: 3 AN: 1144896 Hom.: 0 Cov.: 31 AF XY: 0.00000365 AC XY: 2 AN XY: 548150

African (AFR) AF: 0.00 AC: 0 AN: 23126

American (AMR) AF: 0.00 AC: 0 AN: 9192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15486

East Asian (EAS) AF: 0.00 AC: 0 AN: 26456

South Asian (SAS) AF: 0.00 AC: 0 AN: 36058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3124

European-Non Finnish (NFE) AF: 0.00000313 AC: 3 AN: 958906

Other (OTH) AF: 0.00 AC: 0 AN: 46774

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 289 of the KCNH2 protein (p.Glu289Gln). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 1764220). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Cardiovascular phenotype Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E289Q variant (also known as c.865G>C), located in coding exon 4 of the KCNH2 gene, results from a G to C substitution at nucleotide position 865. The glutamic acid at codon 289 is replaced by glutamine, an amino acid with highly 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
CardioboostArm	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;.
PhyloP100		1.7
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.3	N;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0080	D;.
Sift4G	Benign	0.37	T;T
Polyphen		0.97	D;.
Vest4		0.22
MutPred		0.49		Gain of MoRF binding (P = 0.0297);.;
MVP		0.94
MPC		1.8
ClinPred		0.90	D
GERP RS		3.8
Varity_R		0.28
gMVP		0.66
Mutation Taster		=17/83	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: rs199472880; hg19: chr7-150655198;