NM_002241.5(KCNJ10):c.1043G>A (p.Arg348His) AND EAST syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 25, 2022
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:: RCV000461889.22

Allele description [Variation Report for NM_002241.5(KCNJ10):c.1043G>A (p.Arg348His)]

NM_002241.5(KCNJ10):c.1043G>A (p.Arg348His)

Gene:

KCNJ10:potassium inwardly rectifying channel subfamily J member 10 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q23.2

Genomic location:

Preferred name:

NM_002241.5(KCNJ10):c.1043G>A (p.Arg348His)

Other names:

p.R348H:CGC>CAC

HGVS:

NC_000001.11:g.160041490C>T
NG_016411.1:g.33682G>A
NM_002241.5:c.1043G>AMANE SELECT
NP_002232.2:p.Arg348His
NC_000001.10:g.160011280C>T
NM_002241.4:c.1043G>A

Protein change:

R348H

Links:

dbSNP: rs146396982

NCBI 1000 Genomes Browser:

rs146396982

Molecular consequence:

NM_002241.5:c.1043G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: EAST syndrome (SESAMES)
Synonyms:: SeSAME syndrome; Seizures, sensorineural deafness, ataxia, mental retardation and electrolyte imbalance; Epilepsy, ataxia, sensorineural deafness and tubulopathy; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013005; MedGen: C2748572; Orphanet: 199343; OMIM: 612780

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RecName: Full=Arabinonate dehydratase
RecName: Full=Arabinonate dehydratase
gi|74538028|sp|Q97U96.1|ARAD_SACS2

Protein
Profile neighbors for GEO Profiles (Select 125837161) (199)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000552192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27677466, 28492532
SCV001255844	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000552192

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 25, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001255844

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 28, 2017)

germline

clinical testing

Citation Link

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

Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy.

Sicca F, Ambrosini E, Marchese M, Sforna L, Servettini I, Valvo G, Brignone MS, Lanciotti A, Moro F, Grottesi A, Catacuzzeno L, Baldini S, Hasan S, D'Adamo MC, Franciolini F, Molinari P, Santorelli FM, Pessia M.

Sci Rep. 2016 Sep 28;6:34325. doi: 10.1038/srep34325.

PubMed [citation]

PMID:: 27677466
PMCID:: PMC5039625

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, SCV000552192.9

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 348 of the KCNJ10 protein (p.Arg348His). This variant is present in population databases (rs146396982, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of KCNJ10-related conditions (PMID: 27677466). ClinVar contains an entry for this variant (Variation ID: 205823). 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 KCNJ10 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNJ10 function (PMID: 27677466). 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 Illumina Laboratory Services, Illumina, SCV001255844.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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: Oct 26, 2024

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