NM_000238.4(KCNH2):c.3404G>A (p.Arg1135His) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002514289.2

Allele description [Variation Report for NM_000238.4(KCNH2):c.3404G>A (p.Arg1135His)]

NM_000238.4(KCNH2):c.3404G>A (p.Arg1135His)

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.3404G>A (p.Arg1135His)

HGVS:

NC_000007.14:g.150945441C>T
NG_008916.1:g.37486G>A
NM_000238.4:c.3404G>AMANE SELECT
NM_172057.3:c.2384G>A
NP_000229.1:p.Arg1135His
NP_000229.1:p.Arg1135His
NP_742054.1:p.Arg795His
LRG_288t1:c.3404G>A
LRG_288:g.37486G>A
LRG_288p1:p.Arg1135His
NC_000007.13:g.150642529C>T
NM_000238.3:c.3404G>A

Protein change:

R1135H

Links:

dbSNP: rs199473547

NCBI 1000 Genomes Browser:

rs199473547

Molecular consequence:

NM_000238.4:c.3404G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.2384G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV003441182	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18692916, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003441182

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 2, 2022)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel KCNH2 mutation as a modifier for short QT interval.

Itoh H, Sakaguchi T, Ashihara T, Ding WG, Nagaoka I, Oka Y, Nakazawa Y, Yao T, Jo H, Ito M, Nakamura K, Ohe T, Matsuura H, Horie M.

Int J Cardiol. 2009 Sep 11;137(1):83-5. doi: 10.1016/j.ijcard.2008.05.050. Epub 2008 Aug 9.

PubMed [citation]

PMID:: 18692916

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003441182.1

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1135 of the KCNH2 protein (p.Arg1135His). This variant is present in population databases (rs199473547, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 18692916). ClinVar contains an entry for this variant (Variation ID: 67493). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 18692916). 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

Last Updated: Sep 29, 2024

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