11-17387190-C-G

Position:

• chr11-17387190-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000525.4(KCNJ11):​c.902G>C​(p.Arg301Pro) 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. 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. R301H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNJ11 NM_000525.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• 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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17387190-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 11-17387190-C-G is Pathogenic according to our data. Variant chr11-17387190-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 847800.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ11	NM_000525.4	c.902G>C	p.Arg301Pro	missense_variant	1/1	ENST00000339994.5	NP_000516.3
KCNJ11	NM_001166290.2	c.641G>C	p.Arg214Pro	missense_variant	2/2		NP_001159762.1
KCNJ11	NM_001377296.1	c.641G>C	p.Arg214Pro	missense_variant	3/3		NP_001364225.1
KCNJ11	NM_001377297.1	c.641G>C	p.Arg214Pro	missense_variant	2/2		NP_001364226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ11	ENST00000339994.5	c.902G>C	p.Arg301Pro	missense_variant	1/1	6	NM_000525.4	ENSP00000345708.4
KCNJ11	ENST00000528731.1	c.641G>C	p.Arg214Pro	missense_variant	2/2	1		ENSP00000434755.1
KCNJ11	ENST00000682350.1	c.641G>C	p.Arg214Pro	missense_variant	2/2			ENSP00000508090.1
KCNJ11	ENST00000682764.1	c.641G>C	p.Arg214Pro	missense_variant	2/3			ENSP00000506780.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2019

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg301 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14715863, 15562009, 23275527, 23345197, 18250167, 20685672). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect KCNJ11 protein function (PMID: 18250167). This variant has been observed in individual(s) with familial hyperinsulinism (PMID: 18250167, 21115269, 28787272). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 301 of the KCNJ11 protein (p.Arg301Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jun 29, 2018

ACMG criteria: PP3 (11 predictors; Revel score 0.984), PM2 = VUS Variant found in homozygous state in patients with congenital hyperinsulinism (PMID: 18250167, 21115269- PGD paper); c.902G>A/p.Arg301His/rs74339567 (PMID: 15562009, 16357843- focal hyperinsulinism); Variant shown to be LOF (PMID: 18250167), which is consistent with hyperinsulinemia. GOF mutations cause DM -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;.
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.97
MutPred		0.90		Gain of glycosylation at T298 (P = 0.0274);.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.98

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: rs74339576; hg19: chr11-17408737;