11-17387491-G-A

Position:

• chr11-17387491-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000525.4
• 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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8666.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=8, not_provided=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ11	NM_000525.4	c.601C>T	p.Arg201Cys	missense_variant	1/1	ENST00000339994.5
KCNJ11	NM_001166290.2	c.340C>T	p.Arg114Cys	missense_variant	2/2
KCNJ11	NM_001377296.1	c.340C>T	p.Arg114Cys	missense_variant	3/3
KCNJ11	NM_001377297.1	c.340C>T	p.Arg114Cys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ11	ENST00000339994.5	c.601C>T	p.Arg201Cys	missense_variant	1/1		NM_000525.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neonatal diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Madras Diabetes Research Foundation

-

- -

Diabetes mellitus, permanent neonatal 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Diabetes mellitus, transient neonatal, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 28, 2020

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

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. -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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

not provided, no classification provided

literature only

GeneReviews

-

- -

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
MutationTaster	Benign	1.0	A;A
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;