NM_000891.3(KCNJ2):c.616G>A (p.Gly206Ser) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 19, 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:: RCV000644781.8

Allele description [Variation Report for NM_000891.3(KCNJ2):c.616G>A (p.Gly206Ser)]

NM_000891.3(KCNJ2):c.616G>A (p.Gly206Ser)

Gene:

KCNJ2:potassium inwardly rectifying channel subfamily J member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q24.3

Genomic location:

Preferred name:

NM_000891.3(KCNJ2):c.616G>A (p.Gly206Ser)

HGVS:

NC_000017.11:g.70175655G>A
NG_008798.1:g.11121G>A
NM_000891.3:c.616G>AMANE SELECT
NP_000882.1:p.Gly206Ser
NP_000882.1:p.Gly206Ser
LRG_328t1:c.616G>A
LRG_328:g.11121G>A
LRG_328p1:p.Gly206Ser
NC_000017.10:g.68171796G>A
NM_000891.2:c.616G>A

Protein change:

G206S

Links:

dbSNP: rs141035459

NCBI 1000 Genomes Browser:

rs141035459

Molecular consequence:

NM_000891.3:c.616G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Andersen Tawil syndrome (LQT7)
Synonyms:: Andersen Syndrome; Andersen cardiodysrhythmic periodic paralysis; Long QT syndrome 7; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008222; MedGen: C1563715; Orphanet: 37553; OMIM: 170390

Name:: Short QT syndrome type 3
Identifiers:: MONDO: MONDO:0012314; MedGen: C1865018; Orphanet: 51083; OMIM: 609622

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000766495	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 19, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23631430, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000766495

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 19, 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

Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory.

Lieve KV, Williams L, Daly A, Richard G, Bale S, Macaya D, Chung WK.

Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. doi: 10.1089/gtmb.2012.0118. Epub 2013 Apr 30.

PubMed [citation]

PMID:: 23631430

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000766495.7

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 206 of the KCNJ2 protein (p.Gly206Ser). This variant is present in population databases (rs141035459, gnomAD 0.008%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of KCNJ2-related conditions (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 281601). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNJ2 protein function with a negative predictive value of 80%. 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

Last Updated: Sep 29, 2024

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