rs1060499872

chr7-150947379-G-GGCC

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PM4_Supporting BS2

The NM_000238.4(KCNH2):c.3100_3101insGGC(p.Arg1033dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,548,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: KCNH2 NM_000238.4 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• 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 -1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000238.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000238.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High AC in GnomAd at 7 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.3100_3101insGGC	p.Arg1033dup	inframe_insertion	13/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.3100_3101insGGC	p.Arg1033dup	inframe_insertion	13/15	1	NM_000238.4	P1
KCNH2	ENST00000330883.9	c.2080_2081insGGC	p.Arg693dup	inframe_insertion	9/11	1
KCNH2	ENST00000684241.1	n.3933_3934insGGC		non_coding_transcript_exon_variant	11/13

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000136 AC: 19 AN: 1396446 Hom.: 0 Cov.: 35 AF XY: 0.0000116 AC XY: 8 AN XY: 688866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000158

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74294

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2020	Reported as c.3101_3103insGGC, due to alternate nomenclature, in one individual referred for LQTS genetic testing (Kapplinger et al., 2009); In-frame insertion of 1 amino acid in a non-repeat region; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 402997; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19716085) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	KCNH2: PM2, PM4 -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 11, 2022	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 23, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in 1 proband -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This variant, c.3098_3100dup, results in the insertion of 1 amino acid(s) of the KCNH2 protein (p.Arg1033dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has been observed in individual(s) with Long QT syndrome (PMID: 19716085). This variant is also known as c.3101_3103insGGC (p.1034insR). ClinVar contains an entry for this variant (Variation ID: 402997). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2021

The c.3098_3100dupGGC variant (also known as p.R1033dup) is located in coding exon 13 of the KCNH2 gene. This variant results from an in-frame duplication of GGC at nucleotide positions 3098 to 3100. This results in the duplication of an arginine residue at codon 1033. This amino acid position is well conserved in available vertebrate species. In a study of long QT syndrome clinical genetic testing, this alteration (referred to as c.3101_3103insGGC, p.1034insR) was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 06, 2021

- -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 20, 2023

This variant causes a duplication of one amino acid at codon 1033 in the KCNH2 protein. To our knowledge, functional studies have not been reported for this variant. This variant (as known as c.3101_3103insGGC; p.1034insR) has been reported in an individual suspected of having long QT syndrome (PMID: 19716085). This variant has been identified in 4/31294 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 v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060499872; hg19: chr7-150644467;