NM_000238.4(KCNH2):c.343G>A (p.Val115Met) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 6, 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:: RCV000226122.13

Allele description [Variation Report for NM_000238.4(KCNH2):c.343G>A (p.Val115Met)]

NM_000238.4(KCNH2):c.343G>A (p.Val115Met)

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.343G>A (p.Val115Met)

HGVS:

NC_000007.14:g.150959701C>T
NG_008916.1:g.23226G>A
NM_000238.4:c.343G>AMANE SELECT
NM_001406753.1:c.55G>A
NM_001406755.1:c.166G>A
NM_001406756.1:c.55G>A
NM_001406757.1:c.43G>A
NM_172056.3:c.343G>A
NP_000229.1:p.Val115Met
NP_000229.1:p.Val115Met
NP_001393682.1:p.Val19Met
NP_001393684.1:p.Val56Met
NP_001393685.1:p.Val19Met
NP_001393686.1:p.Val15Met
NP_742053.1:p.Val115Met
NP_742053.1:p.Val115Met
LRG_288t1:c.343G>A
LRG_288t2:c.343G>A
LRG_288:g.23226G>A
LRG_288p1:p.Val115Met
LRG_288p2:p.Val115Met
NC_000007.13:g.150656789C>T
NM_000238.3:c.343G>A
NM_172056.2:c.343G>A
NR_176254.1:n.751G>A

Protein change:

V115M

Links:

dbSNP: rs150988911

NCBI 1000 Genomes Browser:

rs150988911

Molecular consequence:

NM_000238.4:c.343G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.55G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.55G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.43G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.343G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

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RBBP1 (0)
Protein Family Models
c4b [Scophthalmus maximus]
c4b [Scophthalmus maximus]
Gene ID:118309790

Gene
unnamed protein product [Mus musculus]
unnamed protein product [Mus musculus]
gi|74143359|dbj|BAE24176.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000283985	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 6, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18441445, 25417810, 32475984, 28492532
SCV004844072	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18441445, 25417810, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000283985

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 6, 2023)

germline

clinical testing

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

SCV004844072

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 28, 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	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

A rapid solubility assay of protein domain misfolding for pathogenicity assessment of rare DNA sequence variants.

Anderson CL, Routes TC, Eckhardt LL, Delisle BP, January CT, Kamp TJ.

Genet Med. 2020 Oct;22(10):1642-1652. doi: 10.1038/s41436-020-0842-1. Epub 2020 Jun 1.

PubMed [citation]

PMID:: 32475984
PMCID:: PMC7529867

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000283985.9

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

Description

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. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 115 of the KCNH2 protein (p.Val115Met). This variant is present in population databases (rs150988911, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 18441445). ClinVar contains an entry for this variant (Variation ID: 67496). Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 25417810, 32475984). 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, SCV004844072.1

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

Description

This missense variant replaces valine with methionine at codon 115 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Electrophysiological functional studies suggest that this variant may not impact KCNH2 activity (PMID: 25417810); the clinical relevance of this observation is not known. This variant has been reported in an individual affected with long QT syndrome (PMID: 18441445). This variant has been identified in 4/251426 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		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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