7-150947800-C-T

Variant names:

• chr7-150947800-C-T
• rs199473009
• NM_000238.4:c.2771G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000238.4(KCNH2):​c.2771G>A​(p.Gly924Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,530,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1 O:1
• Conservation: PhyloP100: 1.01

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067821145).
• BS2: High AC in GnomAd4 at 5 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2771G>A	p.Gly924Glu	missense_variant	Exon 12 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2771G>A	p.Gly924Glu	missense_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000330883.9	c.1751G>A	p.Gly584Glu	missense_variant	Exon 8 of 11	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3604G>A		non_coding_transcript_exon_variant	Exon 10 of 13

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000707 AC: 9 AN: 127254 Hom.: 0 AF XY: 0.000101 AC XY: 7 AN XY: 69560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000767

Gnomad SAS 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: 0.0000123 AC: 17 AN: 1378290 Hom.: 0 Cov.: 36 AF XY: 0.0000162 AC XY: 11 AN XY: 679366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000283

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000225

Gnomad4 SAS exome AF: 0.0000511

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000372

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.0000447 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 2 Uncertain:2

Jan 30, 2024

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset and therefore considered benign. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Prediction of the variant by In silico tools to alter splicing and produce an abnormal transcript is uncertain [REVEL: 0.58 (damaging >=0.6, benign <0.4), 3Cnet: 0.23 (damaging >=0.6, benign <0.15), Splice AI: 0.15 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with KCNH2 related disorder (ClinVar ID: VCV000067437 /PMID: 19716085).A different missense change at the same codon (p.Gly924Ala) has been reported to be associated with KCNH2 related disorder (PMID: 19716085). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:2

Dec 13, 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 glycine with glutamic acid at codon 924 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 23338923) and in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been identified in 10/158560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 924 of the KCNH2 protein (p.Gly924Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, 23338923). ClinVar contains an entry for this variant (Variation ID: 67437). 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

Aug 15, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in one individual referred for LQTS genetic testing and in one individual with a normal corrected QT interval who presented with malignant ventricular fibrillation storm (PMID: 19716085, 23338923); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27761165, 23338923, 26704558, 22581653, 26746457, 34026292, 19716085) -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Uncertain:1

Apr 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with glutamic acid at codon 924 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 23338923) and in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been identified in 10/158560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Benign:1

Feb 21, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T
Eigen	Benign	0.013
Eigen_PC	Benign	0.0089
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.068	T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.1	.;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.65	N;N
REVEL	Uncertain	0.58
Sift	Benign	0.45	T;T
Sift4G	Benign	1.0	T;T
Polyphen		1.0	D;D
Vest4		0.44
MutPred		0.76		.;Gain of solvent accessibility (P = 0.024);
MVP		0.99
MPC		0.64
ClinPred		0.17	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs199473009; hg19: chr7-150644888;