NM_000238.4(KCNH2):c.2684C>T (p.Thr895Met) AND Long QT syndrome 2

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jun 10, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000988000.16

Allele description [Variation Report for NM_000238.4(KCNH2):c.2684C>T (p.Thr895Met)]

NM_000238.4(KCNH2):c.2684C>T (p.Thr895Met)

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.2684C>T (p.Thr895Met)

HGVS:

NC_000007.14:g.150948452G>A
NG_008916.1:g.34475C>T
NM_000238.4:c.2684C>TMANE SELECT
NM_172057.3:c.1664C>T
NP_000229.1:p.Thr895Met
NP_000229.1:p.Thr895Met
NP_742054.1:p.Thr555Met
LRG_288t1:c.2684C>T
LRG_288:g.34475C>T
LRG_288p1:p.Thr895Met
NC_000007.13:g.150645540G>A
NM_000238.2:c.2684C>T
NM_000238.3:c.2684C>T

Protein change:

T555M

Links:

dbSNP: rs199473434

NCBI 1000 Genomes Browser:

rs199473434

Molecular consequence:

NM_000238.4:c.2684C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1664C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long QT syndrome 2 (LQT2)
Identifiers:: MONDO: MONDO:0013367; MedGen: C3150943; Orphanet: 101016; Orphanet: 768; OMIM: 613688

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001137544	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001324504	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22581653, 21215473, 18596570, 26332594, 26129877, 23304551, 22995991, 20674198 Citation Link,
SCV002526383	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 10, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26129877, 18596570, 23304551, 21215473, 20674198, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001137544

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV001324504

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 28, 2017)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV002526383

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 10, 2022)

germline

clinical testing

PubMed (6)
[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	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Paralogous annotation of disease-causing variants in long QT syndrome genes.

Ware JS, Walsh R, Cunningham F, Birney E, Cook SA.

Hum Mutat. 2012 Aug;33(8):1188-1191. doi: 10.1002/humu.22114. Epub 2012 Jun 7.

PubMed [citation]

PMID:: 22581653
PMCID:: PMC4640174

Identification of Medically Actionable Secondary Findings in the 1000 Genomes.

Olfson E, Cottrell CE, Davidson NO, Gurnett CA, Heusel JW, Stitziel NO, Chen LS, Hartz S, Nagarajan R, Saccone NL, Bierut LJ.

PLoS One. 2015;10(9):e0135193. doi: 10.1371/journal.pone.0135193.

PubMed [citation]

PMID:: 26332594
PMCID:: PMC4558085

See all PubMed Citations (9)

Details of each submission

From Mendelics, SCV001137544.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001324504.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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 DASA, SCV002526383.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

The c.2684C>T;p.(Thr895Met) missense change has been observed in affected individual(s)(PMID: 26129877; 18596570; 23304551; 21215473; 20674198) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26129877; 18596570) - PS3_supporting. The variant is present at low allele frequencies population databases (rs199473434– gnomAD 0.0005351%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic

#	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		1	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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