NM_000238.4(KCNH2):c.2398+5G>A AND Long QT syndrome 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 5, 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:: RCV002302843.1

Allele description [Variation Report for NM_000238.4(KCNH2):c.2398+5G>A]

NM_000238.4(KCNH2):c.2398+5G>A

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.2398+5G>A

HGVS:

NC_000007.14:g.150950163C>T
NG_008916.1:g.32764G>A
NM_000238.4:c.2398+5G>AMANE SELECT
NM_001204798.2:c.1383G>A
NM_001406755.1:c.2226G>A
NM_001406756.1:c.2115G>A
NM_001406757.1:c.2103G>A
NM_172056.3:c.2403G>A
NM_172057.3:c.1378+5G>A
NP_001191727.1:p.Met461Ile
NP_001393684.1:p.Met742Ile
NP_001393685.1:p.Met705Ile
NP_001393686.1:p.Met701Ile
NP_742053.1:p.Met801Ile
NP_742053.1:p.Met801Ile
LRG_288t2:c.2403G>A
LRG_288:g.32764G>A
LRG_288p2:p.Met801Ile
NC_000007.13:g.150647251C>T
NM_172056.2:c.2403G>A

Protein change:

M461I

Molecular consequence:

NM_000238.4:c.2398+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_172057.3:c.1378+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001204798.2:c.1383G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.2226G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.2115G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.2103G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.2403G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071]

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
SCV002588738	Roden Lab, Vanderbilt University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 5, 2022)	unknown, not applicable	research, in vitro	PubMed (2) [See all records that cite these PMIDs] 25741868, 36197721

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002588738

Roden Lab, Vanderbilt University Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 5, 2022)

unknown, not applicable

research, in vitro

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	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies.

O'Neill MJ, Wada Y, Hall LD, Mitchell DW, Glazer AM, Roden DM.

Circ Genom Precis Med. 2022 Dec;15(6):e003782. doi: 10.1161/CIRCGEN.122.003782. Epub 2022 Oct 5.

PubMed [citation]

PMID:: 36197721
PMCID:: PMC9772980

Details of each submission

From Roden Lab, Vanderbilt University Medical Center, SCV002588738.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	in vitro	PubMed (2)

Description

The KCNH2 variant c.2398+5G>T was observed in 2 cases of LQTS and is absent from large population databases (PMID: 32893267). Splicing predictions were inconclusive for this variant. Minigene functional studies revealed aberrant splicing in the presence of this alternative allele. Collectively, this evidence supports a Likely Pathogenic classification.

#	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
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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