NM_000238.4(KCNH2):c.2665T>G (p.Leu889Val) AND Long QT syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 3, 2024
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:: RCV001088454.17

Allele description

NM_000238.4(KCNH2):c.2665T>G (p.Leu889Val)

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.2665T>G (p.Leu889Val)

Other names:

p.L889V:TTG>GTG

HGVS:

NC_000007.14:g.150948471A>C
NG_008916.1:g.34456T>G
NM_000238.4:c.2665T>GMANE SELECT
NM_172057.3:c.1645T>G
NP_000229.1:p.Leu889Val
NP_000229.1:p.Leu889Val
NP_742054.1:p.Leu549Val
LRG_288t1:c.2665T>G
LRG_288:g.34456T>G
LRG_288p1:p.Leu889Val
NC_000007.13:g.150645559A>C
NM_000238.2:c.2665T>G
NM_000238.3:c.2665T>G

Protein change:

L549V

Links:

dbSNP: rs765427343

NCBI 1000 Genomes Browser:

rs765427343

Molecular consequence:

NM_000238.4:c.2665T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1645T>G - 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
SCV000627465	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Dec 19, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004841746	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 3, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000627465

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Dec 19, 2023)

germline

clinical testing

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

SCV004841746

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 3, 2024)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	24	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

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

Details of each submission

From Invitae, SCV000627465.8

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

#	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, SCV004841746.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	24	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces leucine with valine at codon 889 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 performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 22/279536 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		24	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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