NM_000238.4(KCNH2):c.391G>T (p.Val131Leu) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 17, 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:: RCV001298202.14

Allele description [Variation Report for NM_000238.4(KCNH2):c.391G>T (p.Val131Leu)]

NM_000238.4(KCNH2):c.391G>T (p.Val131Leu)

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.391G>T (p.Val131Leu)

HGVS:

NC_000007.14:g.150959653C>A
NG_008916.1:g.23274G>T
NM_000238.4:c.391G>TMANE SELECT
NM_001406753.1:c.103G>T
NM_001406755.1:c.214G>T
NM_001406756.1:c.103G>T
NM_001406757.1:c.91G>T
NM_172056.3:c.391G>T
NP_000229.1:p.Val131Leu
NP_000229.1:p.Val131Leu
NP_001393682.1:p.Val35Leu
NP_001393684.1:p.Val72Leu
NP_001393685.1:p.Val35Leu
NP_001393686.1:p.Val31Leu
NP_742053.1:p.Val131Leu
NP_742053.1:p.Val131Leu
LRG_288t1:c.391G>T
LRG_288t2:c.391G>T
LRG_288:g.23274G>T
LRG_288p1:p.Val131Leu
LRG_288p2:p.Val131Leu
NC_000007.13:g.150656741C>A
NM_000238.2:c.391G>T
NM_000238.3:c.391G>T
NM_172056.2:c.391G>T
NR_176254.1:n.799G>T

Protein change:

V131L

Links:

dbSNP: rs142590566

NCBI 1000 Genomes Browser:

rs142590566

Molecular consequence:

NM_000238.4:c.391G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.103G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.214G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.103G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.91G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.391G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

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Homo sapiens ubiquitin specific protease 45 (USP45), mRNA
Homo sapiens ubiquitin specific protease 45 (USP45), mRNA
gi|14249723|ref|NM_032929.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001487247	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004844069	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 17, 2023)	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

SCV001487247

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 1, 2022)

germline

clinical testing

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

SCV004844069

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 17, 2023)

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	6	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001487247.3

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

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 131 of the KCNH2 protein (p.Val131Leu). This variant is present in population databases (rs142590566, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 927974). 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. 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, SCV004844069.1

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

Description

This missense variant replaces valine with leucine at codon 131 of the KCNH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/282830 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		6	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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