7-150948861-G-A

Variant names:

• chr7-150948861-G-A
• rs773724817
• NM_000238.4:c.2587C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000238.4(KCNH2):​c.2587C>T​(p.Arg863*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,796 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002765976: The most pronounced variant effect results in <10% of normal activity (Teng_2004)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R863R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNH2 NM_000238.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.23
• Publications: 18 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002765976: The most pronounced variant effect results in <10% of normal activity (Teng_2004).; SCV000490553: Published functional studies demonstrate a damaging effect as this variant failed to form functional KCNH2 channels (Teng et al., 2004; Akhavan et al., 2005; Yao et al., 2009); SCV002739188: In an assay testing KCNH2 function, this variant showed a functionally abnormal result (Teng S et al. J Mol Med. 2004;82:189-96; Yao Y et al. Heart Rhythm. 2009;6:553-60).; SCV004848435: In vitro functional studies support an impact on protein function (Teng 2004 PMID: 14714110, Yao 2009 PMID: 19324319).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-150948861-G-A is Pathogenic according to our data. Variant chr7-150948861-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 220208.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.2587C>T	p.Arg863*	stop_gained	Exon 10 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2299C>T	p.Arg767*	stop_gained	Exon 8 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.1567C>T	p.Arg523*	stop_gained	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.2587C>T	p.Arg863*	stop_gained	Exon 10 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1567C>T	p.Arg523*	stop_gained	Exon 6 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.2521C>T	p.Arg841*	stop_gained	Exon 10 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251266 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

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: 0.00 AC: 0 AN: 1111934

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000189 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		1.2
Vest4		0.99
GERP RS		4.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773724817; hg19: chr7-150645949; COSMIC: COSV51136691; COSMIC: COSV51136691;