NM_000238.4(KCNH2):c.967G>A (p.Asp323Asn) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 13, 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:: RCV000691482.11

Allele description [Variation Report for NM_000238.4(KCNH2):c.967G>A (p.Asp323Asn)]

NM_000238.4(KCNH2):c.967G>A (p.Asp323Asn)

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.967G>A (p.Asp323Asn)

HGVS:

NC_000007.14:g.150957452C>T
NG_008916.1:g.25475G>A
NM_000238.4:c.967G>AMANE SELECT
NM_001406753.1:c.679G>A
NM_001406755.1:c.790G>A
NM_001406756.1:c.679G>A
NM_001406757.1:c.667G>A
NM_172056.3:c.967G>A
NP_000229.1:p.Asp323Asn
NP_000229.1:p.Asp323Asn
NP_001393682.1:p.Asp227Asn
NP_001393684.1:p.Asp264Asn
NP_001393685.1:p.Asp227Asn
NP_001393686.1:p.Asp223Asn
NP_742053.1:p.Asp323Asn
NP_742053.1:p.Asp323Asn
LRG_288t1:c.967G>A
LRG_288t2:c.967G>A
LRG_288:g.25475G>A
LRG_288p1:p.Asp323Asn
LRG_288p2:p.Asp323Asn
NC_000007.13:g.150654540C>T
NM_000238.3:c.967G>A
NM_172056.2:c.967G>A
NR_176254.1:n.1375G>A
Q12809:p.Asp323Asn

Protein change:

D223N

Links:

UniProtKB: Q12809#VAR_074807; dbSNP: rs199472887

NCBI 1000 Genomes Browser:

rs199472887

Molecular consequence:

NM_000238.4:c.967G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.679G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.790G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.679G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.667G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.967G>A - 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
SCV000819263	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19716085, 28492532
SCV004844042	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19716085, 26920202, 32893267, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000819263

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 10, 2023)

germline

clinical testing

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

SCV004844042

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

germline

clinical testing

PubMed (4)
[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	5	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

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000819263.6

#	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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 323 of the KCNH2 protein (p.Asp323Asn). This variant is present in population databases (rs199472887, gnomAD 0.01%). This missense change has been observed in individual(s) with Long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67551). 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. 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, SCV004844042.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces aspartic acid with asparagine at codon 323 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant is found within a highly conserved cytoplasmic region (a.a. 1-403). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual suspected long QT syndrome (PMID: 19716085, 26920202). One of these individuals also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (PMID:26920202). This variant has been identified in 7/282048 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		5	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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