NM_000891.3(KCNJ2):c.461G>A (p.Cys154Tyr) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 25, 2019
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:: RCV001230651.2

Allele description [Variation Report for NM_000891.3(KCNJ2):c.461G>A (p.Cys154Tyr)]

NM_000891.3(KCNJ2):c.461G>A (p.Cys154Tyr)

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.461G>A (p.Cys154Tyr)

HGVS:

NC_000017.11:g.70175500G>A
NG_008798.1:g.10966G>A
NM_000891.3:c.461G>AMANE SELECT
NP_000882.1:p.Cys154Tyr
NP_000882.1:p.Cys154Tyr
LRG_328t1:c.461G>A
LRG_328:g.10966G>A
LRG_328p1:p.Cys154Tyr
NC_000017.10:g.68171641G>A
NM_000891.2:c.461G>A

Protein change:

C154Y

Links:

dbSNP: rs199473380

NCBI 1000 Genomes Browser:

rs199473380

Molecular consequence:

NM_000891.3:c.461G>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
SCV001403137	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 25, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15831539, 19570891, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001403137

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 25, 2019)

germline

clinical testing

PubMed (3)
[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

In vivo and in vitro functional characterization of Andersen's syndrome mutations.

Bendahhou S, Fournier E, Sternberg D, Bassez G, Furby A, Sereni C, Donaldson MR, Larroque MM, Fontaine B, Barhanin J.

J Physiol. 2005 Jun 15;565(Pt 3):731-41. Epub 2005 Apr 14.

PubMed [citation]

PMID:: 15831539
PMCID:: PMC1464553

Mechanisms underlying Andersen's syndrome pathology in skeletal muscle are revealed in human myotubes.

Sacconi S, Simkin D, Arrighi N, Chapon F, Larroque MM, Vicart S, Sternberg D, Fontaine B, Barhanin J, Desnuelle C, Bendahhou S.

Am J Physiol Cell Physiol. 2009 Oct;297(4):C876-85. doi: 10.1152/ajpcell.00519.2008. Epub 2009 Jul 1.

PubMed [citation]

PMID:: 19570891

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001403137.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces cysteine with tyrosine at codon 154 of the KCNJ2 protein (p.Cys154Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Andersen-Tawil syndrome (PMID: 19570891, Invitae). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Cys154 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ2-related conditions (PMID: 15831539), which suggests that this may be a clinically significant amino acid residue. 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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