NM_000238.4(KCNH2):c.2707G>A (p.Gly903Arg) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000465531.20

Allele description [Variation Report for NM_000238.4(KCNH2):c.2707G>A (p.Gly903Arg)]

NM_000238.4(KCNH2):c.2707G>A (p.Gly903Arg)

Gene:

KCNH2:potassium voltage-gated channel subfamily H member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_000238.4(KCNH2):c.2707G>A (p.Gly903Arg)

Other names:

p.G903R:GGG>AGG

HGVS:

NC_000007.14:g.150947864C>T
NG_008916.1:g.35063G>A
NM_000238.4:c.2707G>AMANE SELECT
NM_001406753.1:c.2419G>A
NM_172057.3:c.1687G>A
NP_000229.1:p.Gly903Arg
NP_000229.1:p.Gly903Arg
NP_001393682.1:p.Gly807Arg
NP_742054.1:p.Gly563Arg
NP_742054.1:p.Gly563Arg
LRG_288t1:c.2707G>A
LRG_288t3:c.1687G>A
LRG_288:g.35063G>A
LRG_288p1:p.Gly903Arg
LRG_288p3:p.Gly563Arg
NC_000007.13:g.150644952C>T
NM_000238.2:c.2707G>A
NM_000238.3:c.2707G>A
NM_172056.1:c.*2035G>A
NM_172057.2:c.1687G>A
Q12809:p.Gly903Arg

Protein change:

G563R

Links:

UniProtKB: Q12809#VAR_074889; dbSNP: rs199473669

NCBI 1000 Genomes Browser:

rs199473669

Molecular consequence:

NM_000238.4:c.2707G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.2419G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1687G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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rhodanese-like/PpiC domain-containing protein 12, chloroplastic isoform X1 [Cucurbita moschata]
gi|1279809439|ref|XP_022958185.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000543411	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19716085, 27000522, 31557540, 28492532
SCV004841732	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 15, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19716085, 27000522, 31557540, 34002542, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543411

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 27, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004841732

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 15, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	46	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543411.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 903 of the KCNH2 protein (p.Gly903Arg). This variant is present in population databases (rs199473669, gnomAD 0.02%). This missense change has been observed in individual(s) with long QT syndrome or Brugada syndrome (PMID: 19716085, 27000522). ClinVar contains an entry for this variant (Variation ID: 67428). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNH2 function (PMID: 31557540). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004841732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	46	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces glycine with arginine at codon 903 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). Functional studies have shown that this variant does not change protein expression levels and has no or a mild impact on the potassium channel function (PMID: 31557540, 34002542). This variant has been reported in three individuals referred for long QT syndrome genetic testing (PMID: 19716085) and in an individual affected with epilepsy (PMID: 34002542). This variant has also been reported in an individual affected with sudden death, and in a family member who had prolonged QTc (PMID: 27000522). This variant has been identified in 19/157684 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		46	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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