11-17387943-C-T

Position:

• chr11-17387943-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000525.4(KCNJ11):​c.149G>A​(p.Arg50Gln) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.91

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.

• PM1: In a topological_domain Cytoplasmic (size 67) in uniprot entity KCJ11_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000525.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 11-17387943-C-T is Pathogenic according to our data. Variant chr11-17387943-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.149G>A	p.Arg50Gln	missense_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.-16-97G>A		intron_variant			NP_001159762.1
KCNJ11	NM_001377296.1	c.-17+75G>A		intron_variant			NP_001364225.1
KCNJ11	NM_001377297.1	c.-16-97G>A		intron_variant			NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.149G>A	p.Arg50Gln	missense_variant	1/1		NM_000525.4	ENSP00000345708	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the KCNJ11 protein (p.Arg50Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant KCNJ11-related early onset diabetes (PMID: 17635943, 22749773, 32893419, 33409956). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 36431). 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: 16731833). This variant disrupts the p.Arg50Gly amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17635943; Invitae). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2022	Published functional studies demonstrate a reduction in the sensitivity of the K(ATP) channel to inhibition by MgATP causing significantly enhanced whole-cell K(ATP) currents, which is expected to reduce insulin secretion (Girard et al., 2006; Shimomura et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15561897, 28824061, 21953423, 22134088, 18335204, 28667717, 32598018, 32935446, 16609879, 9831713, 18436707, 17635943, 27223594, 26388896, 22826452, 32893419, 27167055, 12213829, 23462667, 16731833, 17021801, 34566892, 22749773, 21352428, 27681997, 32418263, 33409956) -

Neonatal diabetes mellitus Pathogenic:1

Likely 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

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 30, 2023

- -

Diabetes Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS2,PS3,PM2,PP3 -

Permanent neonatal diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 09, 2022

Variant summary: KCNJ11 c.149G>A (p.Arg50Gln) results in a conservative amino acid change located in the Potassium channel, inwardly rectifying, transmembrane domain (IPR040445) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252022 control chromosomes. c.149G>A has been reported in the literature in individuals affected with Neonatal Diabetes Mellitus and was a de-novo occurrence in a subset of these ascertained cases (example, Slingerland_2006, Shimomura_2006, Suzuki_2008, Rica_2007, Flanagan_2006, Pearson_2006, Girard_2006, Garcin_2020). It has also been reported among variants responsive to sulfonylurea treatment (example, Garcin_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced channel ATP sensitivity and increased sensitivity to Mg2+ upon expression of mutant homomeric and heteromeric channels in Xenopus oocytes (example, Shimomura_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.83	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.83
Sift	Benign	0.17	T
Sift4G	Benign	0.37	T
Vest4		0.89
MutPred		0.87		Loss of MoRF binding (P = 0.0197);
MVP		1.0
MPC		1.5
ClinPred		0.95	D
GERP RS		4.6
gMVP		0.75

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: rs80356611; hg19: chr11-17409490;