rs199473004

Variant names:

• chr7-150948938-T-C
• rs199473004
• NM_000238.4:c.2510A>G

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.2510A>G​(p.Asp837Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 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: "SCV000234176: Functional studies have shown that variants in the CNBHD can cause incorrect folding that can lead to protein instability and ultimately deficient protein trafficking (Li et al., 2016" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D837N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 8.01
• Publications: 7 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000234176: Functional studies have shown that variants in the CNBHD can cause incorrect folding that can lead to protein instability and ultimately deficient protein trafficking (Li et al., 2016; Anderson et al., 2014).; SCV003800193: Functional analyses of the variant protein show abnormal trafficking and gating (Anderson 2014). PMID: 25417810; SCV000543440: Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810).; SCV004827270: Experimental analysis of the variant in cultured cell line proved the deficient protein trafficking and the negative functional impact (PMID: 25417810).; SCV002074428: the variant induces a trafficking defect of the mature hERG channel when expressed alone in HEK293 cells, and in a dominant-negative manner when co-expressed with wild-type protein (Anderson_2014). Conformational changes that were detected via NMR spectrometry in E.coli purified protein have been suggested as a cause of this deficiency (Li_2016).; SCV006064585: "A functional study has shown that this variant causes deficient maturation and trafficking of KCNH2 protein to the cell surface in transfected HEK293 cells." PMID:25417810; SCV002745149: Immunoblot data suggest that this variant is a protein trafficking deficient alteration (Anderson CL et al. Nat Commun. 2014;5:5535).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150948939-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.979
• PP5: Variant 7-150948938-T-C is Pathogenic according to our data. Variant chr7-150948938-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67407.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.2510A>G	p.Asp837Gly	missense	Exon 10 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2222A>G	p.Asp741Gly	missense	Exon 8 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.1490A>G	p.Asp497Gly	missense	Exon 6 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2510A>G	p.Asp837Gly	missense	Exon 10 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1490A>G	p.Asp497Gly	missense	Exon 6 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.2444A>G	p.Asp815Gly	missense	Exon 10 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Cardiac arrhythmia (2)
2	-	-	Long QT syndrome (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Long QT syndrome 2 (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.011	D
Sift4G	Benign	0.20	T
Polyphen		0.71	P
Vest4		0.87
MutPred		0.91		Loss of stability (P = 0.0592)
MVP		1.0
MPC		2.5
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.75
gMVP		0.98
Mutation Taster		=3/97	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: rs199473004; hg19: chr7-150646026;