11-128911724-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000890.5(KCNJ5):c.451G>A(p.Gly151Arg) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G151E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNJ5
NM_000890.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 10.0

Publications

142 publications found

Variant links:

Genes affected

KCNJ5 (HGNC:6266): (potassium inwardly rectifying channel subfamily J member 5) This gene encodes an integral membrane protein which belongs to one of seven subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded protein is a subunit of the potassium channel which is homotetrameric. It is controlled by G-proteins and has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Naturally occurring mutations in this gene are associated with aldosterone-producing adenomas. [provided by RefSeq, Aug 2017]

KCNJ5 Gene-Disease associations (from GenCC):

familial hyperaldosteronism type III
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Andersen-Tawil syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
long QT syndrome 13
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
long QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNJ5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 22 ACMG points.

PS1

Transcript NM_000890.5 (KCNJ5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 91916

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000890.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-128911725-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 135679.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 11-128911724-G-A is Pathogenic according to our data. Variant chr11-128911724-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 91915.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
KCNJ5	NM_000890.5 link	c.451G>A	p.Gly151Arg	missense_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3	P48544A0A5J6E2W8
KCNJ5	NM_001354169.2 link	c.451G>A	p.Gly151Arg	missense_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4 link	c.451G>A	p.Gly151Arg	missense_variant	Exon 2 of 3		XP_011541112.1	P48544A0A5J6E2W8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNJ5	ENST00000529694.6 link	c.451G>A	p.Gly151Arg	missense_variant	Exon 2 of 3	1	NM_000890.5	ENSP00000433295.1	P48544
KCNJ5	ENST00000338350.4 link	c.451G>A	p.Gly151Arg	missense_variant	Exon 3 of 4	1		ENSP00000339960.4	P48544
KCNJ5	ENST00000533599.1 link	c.451G>A	p.Gly151Arg	missense_variant	Exon 1 of 2	1		ENSP00000434266.1	P48544

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hyperaldosteronism type III

Pathogenic:2

Aug 16, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 14, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aldosterone-producing adrenal adenoma, somatic

Pathogenic:1

Feb 14, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Richard Lifton Laboratory, Yale University School of Medicine

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Long QT syndrome

Pathogenic:1

Mar 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense change has been observed in individual(s) with clinical features of KCNJ5-related conditions (PMID: 22308486, 24819081). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 151 of the KCNJ5 protein (p.Gly151Arg). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 91915). 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 KCNJ5 protein function. This variant disrupts the p.Gly151 amino acid residue in KCNJ5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22203740, 22308486). 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. -

Cardiovascular phenotype

Pathogenic:1

Jun 08, 2018

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G151R pathogenic mutation (also known as c.451G>A), located in coding exon 1 of the KCNJ5 gene, results from a G to A substitution at nucleotide position 451. The glycine at codon 151 is replaced by arginine, an amino acid with dissimilar properties. This alteration impacts the highly conserved ion selectivity filter (TIGYGF) located between transmembrane helices S5 and S6. This variant has been identified in multiple individuals with familial hyperaldosteronism type III (FH-III) and was reported to be de novo in several of them (Scholl UI et al. Proc. Natl. Acad. Sci. U.S.A. 2012;109:2533-8; Adachi M et al. Horm Res Paediatr. 2014;82:138-42; Monticone S et al. J Hum Hypertens. 2017;31:776-781). Functional studies suggest G151R leads to increased sodium conductance (Scholl UI et al. Proc. Natl. Acad. Sci. U.S.A. 2012;109:2533-8; Tauber P et al. Endocrinology. 2014;155:1353-62). In addition, internal structural analysis indicates that this variant disrupts the ion channel pore and is expected to eliminate the K+ selectivity of the K+ channel (Tao X et al. Science. 2009;326(5960):1668-74; Whorton MR and MacKinnon R. Cell. 2011;147(1):199-208; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;.;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

1.0

D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.0

H;H;H

PhyloP100

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.7

D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.98

MutPred

0.97

Loss of glycosylation at T149 (P = 0.0803);Loss of glycosylation at T149 (P = 0.0803);Loss of glycosylation at T149 (P = 0.0803);

MVP

0.98

MPC

1.4

ClinPred

1.0

GERP RS

5.5

Varity_R

0.96

gMVP

1.0

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over