NM_000238.4(KCNH2):c.2954A>G (p.Asn985Ser) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 9, 2023
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:: RCV000698170.15

Allele description [Variation Report for NM_000238.4(KCNH2):c.2954A>G (p.Asn985Ser)]

NM_000238.4(KCNH2):c.2954A>G (p.Asn985Ser)

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.2954A>G (p.Asn985Ser)

HGVS:

NC_000007.14:g.150947617T>C
NG_008916.1:g.35310A>G
NM_000238.4:c.2954A>GMANE SELECT
NM_172057.3:c.1934A>G
NP_000229.1:p.Asn985Ser
NP_000229.1:p.Asn985Ser
NP_742054.1:p.Asn645Ser
LRG_288t1:c.2954A>G
LRG_288:g.35310A>G
LRG_288p1:p.Asn985Ser
NC_000007.13:g.150644705T>C
NM_000238.3:c.2954A>G

Protein change:

N645S

Links:

dbSNP: rs199473541

NCBI 1000 Genomes Browser:

rs199473541

Molecular consequence:

NM_000238.4:c.2954A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1934A>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000826815	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 16, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16043162, 28492532
SCV004835896	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 9, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16043162, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000826815

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 16, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004835896

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 9, 2023)

germline

clinical testing

PubMed (2)
[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	1	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

Role of sequence variations in the human ether-a-go-go-related gene (HERG, KCNH2) in the Brugada syndrome.

Verkerk AO, Wilders R, Schulze-Bahr E, Beekman L, Bhuiyan ZA, Bertrand J, Eckardt L, Lin D, Borggrefe M, Breithardt G, Mannens MM, Tan HL, Wilde AA, Bezzina CR.

Cardiovasc Res. 2005 Dec 1;68(3):441-53. Epub 2005 Jul 25.

PubMed [citation]

PMID:: 16043162

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000826815.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. Experimental studies have shown that this missense change results in a protein with most, but not all function retained (PMID: 16043162). This variant has been reported in an individual affected with Brugada syndrome (PMID: 16043162). ClinVar contains an entry for this variant (Variation ID: 67456). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 985 of the KCNH2 protein (p.Asn985Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine.

#	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, SCV004835896.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces asparagine with serine at codon 985 of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental study has shown that the variant does not significantly biophysical properties of the potassium channels, except for voltage-dependence of inactivation and current densities (PMID: 16043162). Clinical relevance of this observation is not clear. This variant has been reported in an individual affected with Brugada syndrome (PMID: 16043162). This variant has also been identified in 2/277014 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.

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

Last Updated: Nov 3, 2024

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