7-150950921-C-T

Position:

• chr7-150950921-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000238.4(KCNH2):​c.2145G>A​(p.Ala715=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNH2 NM_000238.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 0.591

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 7-150950921-C-T is Pathogenic according to our data. Variant chr7-150950921-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200415.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3, Pathogenic=1}. Variant chr7-150950921-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2145G>A	p.Ala715=	splice_region_variant, synonymous_variant	8/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2145G>A	p.Ala715=	splice_region_variant, synonymous_variant	8/15	1	NM_000238.4	ENSP00000262186	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461698 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KCNH2: PM2, PS4:Moderate, PS3:Supporting, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2020	Observed in several individuals with a prolonged QT interval and/or LQTS in published literature (Tester et al., 2005; Kapa et al., 2009; Kapplinger et al., 2009; Mitchel et al., 2012; Cuneo et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 200415; Landrum et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 19716085, 23124029, 19841300, 15840476, 23995044) -

Long QT syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

in vitro;research

Roden Lab, Vanderbilt University Medical Center

Oct 05, 2022

The KCNH2 variant c.2145G>A was observed in 2 cases of LQTS and is absent from large population databases (PMID: 32893267). Minigene functional studies revealed aberrant splicing in the presence of this alternative allele. Collectively, this evidence supports a Likely Pathogenic classification. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 05, 2023

This sequence change affects codon 715 of the KCNH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KCNH2 protein. This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (rs794728384, gnomAD 0.0009%). This variant has been observed in individuals with long QT syndrome (PMID: 19716085, 19841300; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200415). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 36197721). For these reasons, this variant has been classified as Pathogenic. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 21, 2023

This synonymous variant alters the conserved c.G at the last nucleotide of exon 8 of the KCNH2 gene. A functional study with minigene assay has shown that this variant causes significantly increased exon 8 skipping while a reduction of canonical transcript compared to wild type control (PMID: 36197721). As a result, this variant creates a frameshift and premature translation stop signal and is expected to result in an absent or non-functional protein product. This variant has been reported in at least six unrelated individuals affected with long QT syndrome (PMID: 19841300, 23124029, 23382499, 23995044, 32893267, 36138163, ClinVar SCV000543451.7) and in a few individuals suspected of having long QT syndrome (PMID: 19716085). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2017

The c.2145G>A variant (also known as p.A715A), located in coding exon 8 of the KCNH2 gene, results from a G to A substitution at nucleotide position 2145. This nucleotide substitution does not change the at codon 715. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This alteration was reported in patients from long QT syndrome (LQTS) testing cohorts; however, clinical details were limited (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Kapa S et al. Circulation, 2009 Nov;120:1752-60). This alteration was also reported in family members of a sudden arrhythmic death case, as well as in an individual with QTc of 465ms and a history of fetal bradycardia (McGorrian C et al. Europace, 2013 Jul;15:1050-8; Cuneo BF et al. Circ Arrhythm Electrophysiol, 2013 Oct;6:946-51). This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	24
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -23

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728384; hg19: chr7-150648009;