11-17387490-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000525.4(KCNJ11):c.602G>A(p.Arg201His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNJ11
NM_000525.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10U:1O:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

KCNJ11 (HGNC:6257): (potassium inwardly rectifying channel subfamily J member 11) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and is found associated with the sulfonylurea receptor SUR. Mutations in this gene are a cause of familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion. Defects in this gene may also contribute to autosomal dominant non-insulin-dependent diabetes mellitus type II (NIDDM), transient neonatal diabetes mellitus type 3 (TNDM3), and permanent neonatal diabetes mellitus (PNDM). Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2009]

KCNJ11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17387491-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 11-17387490-C-T is Pathogenic according to our data. Variant chr11-17387490-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17387490-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4 link	c.602G>A	p.Arg201His	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3	Q14654-1B2RC52
KCNJ11	NM_001166290.2 link	c.341G>A	p.Arg114His	missense_variant	Exon 2 of 2		NP_001159762.1	Q14654-2A0A804HHV7
KCNJ11	NM_001377296.1 link	c.341G>A	p.Arg114His	missense_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1 link	c.341G>A	p.Arg114His	missense_variant	Exon 2 of 2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5 link	c.602G>A	p.Arg201His	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4		Q14654-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459906

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726302

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Aug 25, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. Additionally, there is evidence that this variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiment showed reduced sensitivity to ATP (PMID:15718250). -

Aug 11, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 201 of the KCNJ11 protein (p.Arg201His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neonatal diabetes (PMID: 15115830, 15531505, 15838686, 16670688, 24622368). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8666). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 15115830). This variant disrupts the p.Arg201 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15115830, 22768671, 26958039, 27681997). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published in vitro functional studies suggest a damaging effect due to reduced ATP sensitivity leading to a loss of insulin secretion in response to metabolic stimulation (Tarasov et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); 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: 16205880, 34566892, 16339180, 20220270, 25308342, 20466780, 20540435, 21352428, 26839896, 23434183, 23959658, 15838686, 15531505, 28460053, 16670688, 25028140, 18924582, 28480665, 19345438, 19500515, 18548275, 19247925, 32792356, 32418263, 33837025, 33240318, 30094785, 15115830, 16731837, 23462667, 16087682, 24622368, 17065345, 32893419, 33663443, 33885251, 36418577, 34671977, 37251668) -

Diabetes mellitus, permanent neonatal 2

Pathogenic:2

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.602G>A (p.Arg201His) missense variant in KCNJ11 gene has been reported in individual(s) with neonatal diabetes (Gloyn et al., 2006). In at least one individual the variant was observed to be de novo. Experimental studies have shown that this missense change affects KCNJ11 function (Gloynet al., 2004). This variant disrupts the p.Arg201Cys amino acid residue in KCNJ11. The p.Arg201His variant is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 201 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg201His in KCNJ11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as likely Pathogenic. -

Jul 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neonatal diabetes mellitus

Pathogenic:1

Molecular Genetics, Madras Diabetes Research Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neonatal insulin-dependent diabetes mellitus

Pathogenic:1

May 03, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diabetes mellitus, transient neonatal, 3

Pathogenic:1

Jul 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hyperinsulinemia

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

Mutations in KCNJ11 gene can generally cause decreased production and secretion of insulin. This can lead to MODY. However, this particular variant (rs80356624) prevalence is seen in congenital hyperinsulinism and no sufficient evidence is seen to ascertain its significance in MODY yet. -

Permanent neonatal diabetes mellitus

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

D;.;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;.

Vest4

0.98

MutPred

0.99

Loss of MoRF binding (P = 0.0149);.;.;

MVP

1.0

MPC

1.8

ClinPred

1.0

GERP RS

5.2

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over