NM_000525.4(KCNJ11):c.185C>T (p.Thr62Met) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 17, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV002461253.3

Allele description [Variation Report for NM_000525.4(KCNJ11):c.185C>T (p.Thr62Met)]

NM_000525.4(KCNJ11):c.185C>T (p.Thr62Met)

Gene:

KCNJ11:potassium inwardly rectifying channel subfamily J member 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.1

Genomic location:

Preferred name:

NM_000525.4(KCNJ11):c.185C>T (p.Thr62Met)

HGVS:

NC_000011.10:g.17387907G>A
NG_012446.1:g.5753C>T
NM_000525.4:c.185C>TMANE SELECT
NM_001166290.2:c.-16-61C>T
NM_001377296.1:c.-16-61C>T
NM_001377297.1:c.-16-61C>T
NP_000516.3:p.Thr62Met
NP_000516.3:p.Thr62Met
NC_000011.9:g.17409454G>A
NC_000011.9:g.17409454G>A
NM_000525.3:c.185C>T

Protein change:

T62M

Links:

dbSNP: rs1057518775

NCBI 1000 Genomes Browser:

rs1057518775

Molecular consequence:

NM_001166290.2:c.-16-61C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001377296.1:c.-16-61C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001377297.1:c.-16-61C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000525.4:c.185C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002756645	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 16, 2022)	germline	clinical testing	Citation Link,
SCV004295366	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23275527, 24401662, 25201519, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002756645

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 16, 2022)

germline

clinical testing

Citation Link,

SCV004295366

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 17, 2023)

germline

clinical testing

PubMed (4)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.

Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A.

J Clin Endocrinol Metab. 2013 Feb;98(2):E355-63. doi: 10.1210/jc.2012-2169. Epub 2012 Dec 28.

PubMed [citation]

PMID:: 23275527
PMCID:: PMC3565119

Clinical and genetic evaluation of patients with KATP channel mutations from the German registry for congenital hyperinsulinism.

Mohnike K, Wieland I, Barthlen W, Vogelgesang S, Empting S, Mohnike W, Meissner T, Zenker M.

Horm Res Paediatr. 2014;81(3):156-68. doi: 10.1159/000356905. Epub 2014 Jan 7.

PubMed [citation]

PMID:: 24401662

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV002756645.1

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32935446, 22701567, 15718250, 20642364, 15580558, 25201519, 24401662)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004295366.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. 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 expected to disrupt KCNJ11 protein function. ClinVar contains an entry for this variant (Variation ID: 435559). This missense change has been observed in individuals with autosomal recessive congenital hyperinsulinism (PMID: 23275527, 24401662, 25201519). This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 62 of the KCNJ11 protein (p.Thr62Met).

#	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 13, 2024

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