NM_000525.4:c.601C>T

Variant names:

• chr11-17387491-G-A
• rs80356625
• NM_000525.4:c.601C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000525.4(KCNJ11):​c.601C>T​(p.Arg201Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 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. R201H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 B:1 O:1
• Conservation: PhyloP100: 5.77

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]

ACMG classification

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 chr11-17387490-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-17387491-G-A is Pathogenic according to our data. Variant chr11-17387491-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17387491-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.601C>T	p.Arg201Cys	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.340C>T	p.Arg114Cys	missense_variant	Exon 2 of 2		NP_001159762.1
KCNJ11	NM_001377296.1	c.340C>T	p.Arg114Cys	missense_variant	Exon 3 of 3		NP_001364225.1
KCNJ11	NM_001377297.1	c.340C>T	p.Arg114Cys	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	c.601C>T	p.Arg201Cys	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Benign:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neonatal diabetes mellitus Pathogenic:1

-

Molecular Genetics, Madras Diabetes Research Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diabetes mellitus, permanent neonatal 2 Pathogenic:1

Jan 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Diabetes mellitus Pathogenic:1

Feb 08, 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

Feb 28, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 19, 2023

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 cysteine, which is neutral and slightly polar, at codon 201 of the KCNJ11 protein (p.Arg201Cys). 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, 22768671, 26958039, 27681997). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8668). 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%. Studies have shown that this missense change alters KCNJ11 gene expression (PMID: 16731837). This variant disrupts the p.Arg201 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ11-related conditions (PMID: 15115830, 27681997), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Diabetes mellitus, transient neonatal, 3;C5394296:Diabetes mellitus, permanent neonatal 2 Pathogenic:1

Sep 10, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A KCNJ11 c.601C>T (p.Arg201Cys) variant was identified in a heterozygous state. This variant has been reported in numerous individuals with neonatal diabetes both in an inherited and in a de novo state (Chai-Udom R et al., PMID: 27428845; Dupont J et al., PMID: 22768671; Gloyn AL et al., PMID: 15292329; Gloyn AL et al., PMID: 15115830; Hashimoto Y et al., PMID: 27681997). It has been reported in the ClinVar database as a pathogenic variant by four submitters (ClinVar variation ID: 8668) and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KCNJ11 function. In support of this prediction, functional studies show a reduction of channel ATP sensitivity but also impaired channel expression at the cell surface (Lin CW et al., PMID: 16731837). Other variants in the same codon, p.Arg201His and p.Arg201Gly, have been reported in affected individuals and are considered pathogenic (Gloyn AL et al., PMID: 15115830; Hashimoto Y et al., PMID: 27681997; ClinVar variation ID: 8666). Based on the available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the KCNJ11 c.601C>T (p.Arg201Cys) variant is classified as pathogenic. -

Maturity onset diabetes mellitus in young 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 cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. Though the prevalence of this particular variant rs80356625 is seen in neonatal diabetes and hyperinsulinism, no sufficient evidence found for its significance in MODY yet. -

Transitory neonatal diabetes mellitus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: flagged submission

Collection Method: research

Mutations in KCNJ11 can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. The prevalence of this particular variant rs80356625 is seen in neonatal diabetes and hyperinsulinism. However, since the variant is too frequent in different ethnic groups to cause the disease, it is categorized as a benign variant. -

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	0.92
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D;.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Vest4		0.96
MutPred		0.98		Loss of MoRF binding (P = 0.0054);.;.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs80356625; hg19: chr11-17409038;