NM_000238.4:c.157G>C

Variant names:

• chr7-150974861-C-G
• rs199472842
• NM_000238.4:c.157G>C

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.157G>C​(p.Gly53Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004848212: "In vitro functional studies provide some evidence that the p.Gly53Arg variant may impact protein trafficking, although effects of the variant on gating potential are conflicting (Chen 1999, Gianulis 2011, Harley 2012, Anderson 2014)."; SCV002504263: Published functional studies demonstrate a damaging effect via channel deactivation or trafficking defect (Chen et al., 1999; Harley et al., 2012; Anderson et al., 2014); SCV000913628: Functional studies have shown that the mutant protein is defective for protein maturation and trafficking to the cell surface (PMID:22396785, 25417810, 26958806), but shows normal function if successfully transported to the cell surface (PMID:26958806).; SCV002710098: Functional studies indicate that this alteration will impact protein function (Chen J et al. J. Biol. Chem., 1999 Apr;274:10113-8; Gianulis EC et al. J. Biol. Chem., 2011 Jun;286:22160-9; Anderson CL et al. Nat Commun, 2014 Nov;5:5535).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G53C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 6.03
• Publications: 19 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), G2P, 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: 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: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004848212: "In vitro functional studies provide some evidence that the p.Gly53Arg variant may impact protein trafficking, although effects of the variant on gating potential are conflicting (Chen 1999, Gianulis 2011, Harley 2012, Anderson 2014)."; SCV002504263: Published functional studies demonstrate a damaging effect via channel deactivation or trafficking defect (Chen et al., 1999; Harley et al., 2012; Anderson et al., 2014); SCV000913628: Functional studies have shown that the mutant protein is defective for protein maturation and trafficking to the cell surface (PMID: 22396785, 25417810, 26958806), but shows normal function if successfully transported to the cell surface (PMID: 26958806).; SCV002710098: Functional studies indicate that this alteration will impact protein function (Chen J et al. J. Biol. Chem., 1999 Apr;274:10113-8; Gianulis EC et al. J. Biol. Chem., 2011 Jun;286:22160-9; Anderson CL et al. Nat Commun, 2014 Nov;5:5535).
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150974861-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1499003.
• 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, 0.995
• PP5: Variant 7-150974861-C-G is Pathogenic according to our data. Variant chr7-150974861-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.157G>C	p.Gly53Arg	missense	Exon 2 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_172056.3		c.157G>C	p.Gly53Arg	missense	Exon 2 of 9	NP_742053.1	Q12809-5
	KCNH2	NM_001406755.1		c.-21G>C		5_prime_UTR	Exon 2 of 9	NP_001393684.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.157G>C	p.Gly53Arg	missense	Exon 2 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.157G>C	p.Gly53Arg	missense	Exon 2 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000945647.1		c.157G>C	p.Gly53Arg	missense	Exon 2 of 14	ENSP00000615706.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Cardiac arrhythmia (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Congenital long QT syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.93
Sift	Benign	0.043	D
Sift4G	Uncertain	0.060	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.96		Loss of catalytic residue at S55 (P = 0.0804)
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.75
gMVP		0.99
Mutation Taster		=9/91	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

Other links and lift over

dbSNP: rs199472842; hg19: chr7-150671949;