NM_000218.3(KCNQ1):c.844C>G (p.Leu282Val) AND Cardiac arrhythmia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 2, 2023
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:: RCV001842669.12

Allele description [Variation Report for NM_000218.3(KCNQ1):c.844C>G (p.Leu282Val)]

NM_000218.3(KCNQ1):c.844C>G (p.Leu282Val)

Gene:

KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000218.3(KCNQ1):c.844C>G (p.Leu282Val)

HGVS:

NC_000011.10:g.2572909C>G
NG_008935.1:g.132919C>G
NM_000218.3:c.844C>GMANE SELECT
NM_001406836.1:c.844C>G
NM_001406837.1:c.574C>G
NM_181798.2:c.463C>G
NP_000209.2:p.Leu282Val
NP_000209.2:p.Leu282Val
NP_001393765.1:p.Leu282Val
NP_001393766.1:p.Leu192Val
NP_861463.1:p.Leu155Val
NP_861463.1:p.Leu155Val
LRG_287t1:c.844C>G
LRG_287t2:c.463C>G
LRG_287:g.132919C>G
LRG_287p1:p.Leu282Val
LRG_287p2:p.Leu155Val
NC_000011.9:g.2594139C>G
NM_000218.2:c.844C>G
NM_181798.1:c.463C>G
NR_040711.2:n.737C>G

Protein change:

L155V

Links:

dbSNP: rs979241598

NCBI 1000 Genomes Browser:

rs979241598

Molecular consequence:

NM_000218.3:c.844C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.844C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.574C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.463C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiac arrhythmia
Synonyms:: Cardiac rhythm disease
Identifiers:: EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001341077	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 2, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32893267, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001341077

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 2, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Walsh R, Lahrouchi N, Tadros R, Kyndt F, Glinge C, Postema PG, Amin AS, Nannenberg EA, Ware JS, Whiffin N, Mazzarotto F, Škorić-Milosavljević D, Krijger C, Arbelo E, Babuty D, Barajas-Martinez H, Beckmann BM, Bézieau S, Bos JM, Breckpot J, Campuzano O, Castelletti S, et al.

Genet Med. 2021 Jan;23(1):47-58. doi: 10.1038/s41436-020-00946-5. Epub 2020 Sep 7.

PubMed [citation]

PMID:: 32893267
PMCID:: PMC7790744

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 Color Diagnostics, LLC DBA Color Health, SCV001341077.3

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

Description

This missense variant replaces leucine with valine at codon 282 of the KCNQ1 protein. This variant is found within a highly conserved region in transmembrane domain S5 (a.a. a.a. 262-282). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNQ1-related disorders in the literature. 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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