7-150951643-C-T

Variant names:

• chr7-150951643-C-T
• rs199473428
• NM_000238.4:c.1750G>A
• KCNH2 p.Gly584Ser

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 21P and 4B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong BS2

The NM_000238.4(KCNH2):​c.1750G>A​(p.Gly584Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,876 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000731739: "In vitro functional studies provide some evidence that the p.Gly584Ser variant may impact protein function (Zhao 2009)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G584V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 7.72
• Publications: 37 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000731739: "In vitro functional studies provide some evidence that the p.Gly584Ser variant may impact protein function (Zhao 2009)."; SCV000234119: Published functional studies using patch clamp assays in transfected Chinese hamster ovary (CHO) cells and Xenopus oocytes suggest that the G584S mutant channel causes a loss of the rapid delayed rectifier current due to trafficking and gating defects (Zhao et al., 2009; Perry et al., 2016);; SCV000543426: Experimental studies have shown that this missense change affects KCNH2 function (PMID: 19490267).; SCV000738197: "In vitro functional studies have suggested this alteration may have some impact on channel function or protein trafficking." PMID:24076290; SCV001350154: Experimental functional studies have shown that the mutant protein carrying this variant traffics to the cell membrane normally but has moderate impact on the channel function (PMID: 19490267, 26958806).; SCV005900685: Functional studies indicate this variant causes potassium channel gating defects (PMID: 19490267).
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_000238.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150951643-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67263.
• 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, short QT syndrome type 1, short QT syndrome, Brugada syndrome, long QT syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 7-150951643-C-T is Pathogenic according to our data. Variant chr7-150951643-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.1750G>A	p.Gly584Ser	missense	Exon 7 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.1462G>A	p.Gly488Ser	missense	Exon 5 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.1750G>A	p.Gly584Ser	missense	Exon 7 of 9	NP_742053.1	Q12809-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1750G>A	p.Gly584Ser	missense	Exon 7 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.730G>A	p.Gly244Ser	missense	Exon 3 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000461280.2	TSL:1	n.1048G>A		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251412 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000190 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Long QT syndrome 2 (4)
3	-	-	not provided (3)
1	-	-	Cardiac arrhythmia (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Congenital long QT syndrome (2)
1	-	-	KCNH2-related disorder (1)
1	-	-	Long QT syndrome (1)
1	-	-	Short QT syndrome type 1 (1)
1	-	-	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
CardioboostArm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.84	L
PhyloP100		7.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.87
Sift	Benign	0.28	T
Sift4G	Benign	0.24	T
Varity_R		0.54
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199473428;

hg19: chr7-150648731;

COSMIC: COSV51258331;