NM_000238.4(KCNH2):c.985A>G (p.Thr329Ala) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 15, 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:: RCV000793512.10

Allele description [Variation Report for NM_000238.4(KCNH2):c.985A>G (p.Thr329Ala)]

NM_000238.4(KCNH2):c.985A>G (p.Thr329Ala)

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.985A>G (p.Thr329Ala)

HGVS:

NC_000007.14:g.150957434T>C
NG_008916.1:g.25493A>G
NM_000238.4:c.985A>GMANE SELECT
NM_001406753.1:c.697A>G
NM_001406755.1:c.808A>G
NM_001406756.1:c.697A>G
NM_001406757.1:c.685A>G
NM_172056.3:c.985A>G
NP_000229.1:p.Thr329Ala
NP_000229.1:p.Thr329Ala
NP_001393682.1:p.Thr233Ala
NP_001393684.1:p.Thr270Ala
NP_001393685.1:p.Thr233Ala
NP_001393686.1:p.Thr229Ala
NP_742053.1:p.Thr329Ala
NP_742053.1:p.Thr329Ala
LRG_288t1:c.985A>G
LRG_288t2:c.985A>G
LRG_288:g.25493A>G
LRG_288p1:p.Thr329Ala
LRG_288p2:p.Thr329Ala
NC_000007.13:g.150654522T>C
NM_000238.3:c.985A>G
NM_172056.2:c.985A>G
NR_176254.1:n.1393A>G

Protein change:

T229A

Links:

dbSNP: rs946110595

NCBI 1000 Genomes Browser:

rs946110595

Molecular consequence:

NM_000238.4:c.985A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.697A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.808A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.697A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.685A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.985A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000932868	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 5, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004825978	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31696929, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000932868

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 5, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004825978

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Aug 15, 2023)

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	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

Variant frequencies of KCNQ1, KCNH2, and SCN5A in a Chinese inherited arrhythmia cohort and other disease cohorts undergoing genetic testing.

Li X, Liu N, Bai R.

Ann Hum Genet. 2020 Mar;84(2):161-168. doi: 10.1111/ahg.12359. Epub 2019 Nov 7.

PubMed [citation]

PMID:: 31696929

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000932868.4

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

Description

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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KCNH2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 329 of the KCNH2 protein (p.Thr329Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine.

#	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, SCV004825978.1

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

Description

This missense variant replaces threonine with alanine at codon 329 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having epilepsy (PMID: 31696929). This variant has not been identified 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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine