7-150957460-G-C

Variant names:

• chr7-150957460-G-C
• rs199472886
• NM_000238.4:c.959C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PP2 PP3_Moderate BS2

The NM_000238.4(KCNH2):​c.959C>G​(p.Ser320Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 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. S320L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.83
• Publications: 3 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: Likely_benign. The variant received -1 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• BS2: High AC in GnomAdExome4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.959C>G	p.Ser320Trp	missense	Exon 5 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.671C>G	p.Ser224Trp	missense	Exon 3 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.959C>G	p.Ser320Trp	missense	Exon 5 of 9	NP_742053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.959C>G	p.Ser320Trp	missense	Exon 5 of 15	ENSP00000262186.5
	KCNH2	ENST00000713710.1		c.959C>G	p.Ser320Trp	missense	Exon 5 of 15	ENSP00000519013.1
	KCNH2	ENST00000713701.1		c.659C>G	p.Ser220Trp	missense	Exon 4 of 14	ENSP00000519004.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250452 AF XY: 0.00000737

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461722 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:2

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with tryptophan at codon 320 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved cytoplasmic domain (a.a. 1-403). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant does not change potassium channel current (Mattivi et al., 2018). This variant has been reported an individual suspected of long QT syndrome (PMID: 23631430). This variant has been identified in 1/250452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Jun 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 320 of the KCNH2 protein (p.Ser320Trp). This variant is present in population databases (rs199472886, gnomAD 0.0009%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 200312). 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.

not provided Uncertain:1

Mar 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a patient referred for long QT syndrome (LQTS) genetic testing (PMID: 23631430); This variant is associated with the following publications: (PMID: 23631430)

Cardiac arrhythmia Uncertain:1

Sep 14, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with tryptophan at codon 320 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved cytoplasmic domain (a.a. 1-403). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant does not change potassium channel current (Mattivi et al., 2018). This variant has been reported an individual suspected of long QT syndrome (PMID: 23631430). This variant has been identified in 1/250452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostArm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.67		Loss of disorder (P = 6e-04)
MVP		0.95
MPC		2.5
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.54
gMVP		0.82
Mutation Taster		=3/97	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: rs199472886; hg19: chr7-150654548;