NM_000238.4(KCNH2):c.2684C>T (p.Thr895Met) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 16, 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:: RCV000699702.20

Allele description [Variation Report for NM_000238.4(KCNH2):c.2684C>T (p.Thr895Met)]

NM_000238.4(KCNH2):c.2684C>T (p.Thr895Met)

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.2684C>T (p.Thr895Met)

HGVS:

NC_000007.14:g.150948452G>A
NG_008916.1:g.34475C>T
NM_000238.4:c.2684C>TMANE SELECT
NM_172057.3:c.1664C>T
NP_000229.1:p.Thr895Met
NP_000229.1:p.Thr895Met
NP_742054.1:p.Thr555Met
LRG_288t1:c.2684C>T
LRG_288:g.34475C>T
LRG_288p1:p.Thr895Met
NC_000007.13:g.150645540G>A
NM_000238.2:c.2684C>T
NM_000238.3:c.2684C>T

Protein change:

T555M

Links:

dbSNP: rs199473434

NCBI 1000 Genomes Browser:

rs199473434

Molecular consequence:

NM_000238.4:c.2684C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1664C>T - 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
SCV000828425	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 16, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18596570, 26129877, 28492532
SCV004841738	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 30, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18596570, 26129877, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000828425

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 16, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004841738

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 30, 2023)

germline

clinical testing

PubMed (3)
[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

Cardiac ion channel gene mutations in sudden infant death syndrome.

Otagiri T, Kijima K, Osawa M, Ishii K, Makita N, Matoba R, Umetsu K, Hayasaka K.

Pediatr Res. 2008 Nov;64(5):482-7. doi: 10.1203/PDR.0b013e3181841eca.

PubMed [citation]

PMID:: 18596570

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000828425.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 895 of the KCNH2 protein (p.Thr895Met). This variant is present in population databases (rs199473434, gnomAD 0.01%). This missense change has been observed in individual(s) with atrial fibrillation and in two relatives with paroxysmal palpitations (PMID: 18596570, 26129877). ClinVar contains an entry for this variant (Variation ID: 67426). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 18596570, 26129877). 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, SCV004841738.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces threonine with methionine at codon 895 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 electrophysiological study in cell culture has shown that this variant may affect the deactivation time course of the potassium channels (PMID: 26129877). However, clinical relevance of this observation is not clear. This variant has been reported in an individual affected with atrial fibrillation, as well as in the proband's father and son affected with paroxysmal palpitations (PMID: 26129877). This variant has been reported in an infant affected with sudden death syndrome (PMID: 18596570). This variant has also been identified in 6/273882 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. 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		1	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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