NM_000238.4(KCNH2):c.136G>A (p.Asp46Asn) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 18, 2023
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:: RCV003532023.1

Allele description [Variation Report for NM_000238.4(KCNH2):c.136G>A (p.Asp46Asn)]

NM_000238.4(KCNH2):c.136G>A (p.Asp46Asn)

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.136G>A (p.Asp46Asn)

Other names:

p.D46N:GAC>AAC

HGVS:

NC_000007.14:g.150974882C>T
NG_008916.1:g.8045G>A
NM_000238.4:c.136G>AMANE SELECT
NM_001406755.1:c.-42G>A
NM_172056.3:c.136G>A
NP_000229.1:p.Asp46Asn
NP_000229.1:p.Asp46Asn
NP_742053.1:p.Asp46Asn
NP_742053.1:p.Asp46Asn
LRG_288t1:c.136G>A
LRG_288t2:c.136G>A
LRG_288:g.8045G>A
LRG_288p1:p.Asp46Asn
LRG_288p2:p.Asp46Asn
NC_000007.13:g.150671970C>T
NM_000238.2:c.136G>A
NM_000238.3:c.136G>A
NM_172056.2:c.136G>A
NR_176254.1:n.544G>A

Protein change:

D46N

Links:

dbSNP: rs794728408

NCBI 1000 Genomes Browser:

rs794728408

Molecular consequence:

NM_000238.4:c.136G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.136G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Rattus norvegicus RAB27A, member RAS oncogene family, mRNA (cDNA clone MGC:11261...
Rattus norvegicus RAB27A, member RAS oncogene family, mRNA (cDNA clone MGC:112618 IMAGE:7384913), complete cds
gi|68534737|gb|BC098667.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004290503	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30244407, 17905336, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004290503

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 18, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification novel LQT syndrome-associated variants in Polish population and genotype-phenotype correlations in eight families.

Szperl M, Kozicka U, Kosiec A, Kukla P, Roszczynko M, Biernacka EK.

J Appl Genet. 2018 Nov;59(4):463-469. doi: 10.1007/s13353-018-0464-3. Epub 2018 Sep 22.

PubMed [citation]

PMID:: 30244407

Long QT and Brugada syndrome gene mutations in New Zealand.

Chung SK, MacCormick JM, McCulley CH, Crawford J, Eddy CA, Mitchell EA, Shelling AN, French JK, Skinner JR, Rees MI.

Heart Rhythm. 2007 Oct;4(10):1306-14. Epub 2007 Jul 14.

PubMed [citation]

PMID:: 17905336

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004290503.1

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

Description

This variant disrupts the p.Asp46 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 17905336, 30244407), which suggests that this may be a clinically significant amino acid residue. 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. 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. ClinVar contains an entry for this variant (Variation ID: 200551). This missense change has been observed in individual(s) with long QT syndrome (PMID: 17905336). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 46 of the KCNH2 protein (p.Asp46Asn).

#	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: Feb 20, 2024

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