rs954727530

Variant names:

• chr11-17387992-G-A
• rs954727530
• NM_000525.4:c.100C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17387992-G-A
• chr11-17387992-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000525.4(KCNJ11):​c.100C>T​(p.Arg34Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R34H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.85
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• diabetes mellitus, transient neonatal, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hyperinsulinemic hypoglycemia, familial, 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• diabetes mellitus, permanent neonatal 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 13

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal dominant hyperinsulinism due to Kir6.2 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hyperinsulinism due to Kir6.2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 chr11-17387991-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1219242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 11-17387992-G-A is Pathogenic according to our data. Variant chr11-17387992-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.100C>T	p.Arg34Cys	missense_variant	Exon 1 of 1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.-16-146C>T		intron_variant	Intron 1 of 1		NP_001159762.1
KCNJ11	NM_001377296.1	c.-17+26C>T		intron_variant	Intron 2 of 2		NP_001364225.1
KCNJ11	NM_001377297.1	c.-16-146C>T		intron_variant	Intron 1 of 1		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.100C>T	p.Arg34Cys	missense_variant	Exon 1 of 1	6	NM_000525.4	ENSP00000345708.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250946 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461566 Hom.: 0 Cov.: 63 AF XY: 0.00 AC XY: 0 AN XY: 727026

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 07, 2023

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in individuals with transient neonatal diabetes and others with focal congenital hyperinsulinism. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12524280) -

Jul 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg34 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15807877, 24421282, 24686051). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 12524280, 23275527). 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: 557416). This missense change has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 23275527, 27908292). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the KCNJ11 protein (p.Arg34Cys). -

Familial hyperinsulinism Pathogenic:1

Jun 26, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNJ11 c.100C>T (p.Arg34Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4e-06 in 251146 control chromosomes. c.100C>T has been observed in individual(s) affected with Neonatal Diabetes Mellitus and Congenital Hyperinsulinism (examples: Flanagan_2007, Snider_2013, Salomon-Estebanez_2016). These data indicate that the variant may be associated with disease. At least one publication provides experimental evidence evaluating the impact on protein function. The most pronounced effect of the variant was the prevention of channel insertion into the plasma membrane, suggesting that this residue may play a role in the assembly of functional channels (Ribalet_2003). A different variant affecting the same codon has been classified as likely pathogenic (c.101G>A, p.Arg34His), supporting the critical relevance of codon 34 to KCNJ11 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 17446535, 18436707, 18767144, 12524280, 23275527, 27908292). ClinVar contains an entry for this variant (Variation ID: 557416). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Type 2 diabetes mellitus Pathogenic:1

Jan 01, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes Pathogenic:1

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace arginine with cysteine at codon 34 of the KCNJ11 protein, p.(Arg34Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the cytoplasmic N-terminus domain. There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at an allele frequency of 0.0004% (rs954727530, 1/250,946 alleles in gnomAD v2.1). KCNJ11 has a low tolerance for missense variation and missense change is the predominant mutational mechanism (gnomAD v2.1, DECIPHER, ClinVar). Three probands have been described with this variant with transient neonatal diabetes and congenital hyperinsulinism (PMID: 27908292; 23275527; 17446535). Expression studies show a defect in trafficking (PMID: 12524280). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). An alternate change at the same amino acid residue determine to be pathogenic, p.(Arg34His), has been reported in individuals with congenital hyperinsulinism in monoallelic and biallelic forms (PMID: 31218401, 28270372, 24421282, 24686051, 20685672). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM5, PS3_Supporting, PS4_Supporting, PP2, PP3. -

Diabetes mellitus, transient neonatal, 3;C2931833:Hyperinsulinemic hypoglycemia, familial, 2;C5393570:Permanent neonatal diabetes mellitus 1 Pathogenic:1

Mar 24, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
PhyloP100		6.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.93
MutPred		0.92		Loss of disorder (P = 0.0132);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		4.6
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs954727530; hg19: chr11-17409539;