11-128911724-G-A

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

17
1
1

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

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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
KCNJ5NM_000890.5 linkc.451G>A p.Gly151Arg missense_variant Exon 2 of 3 ENST00000529694.6 NP_000881.3 P48544A0A5J6E2W8
KCNJ5NM_001354169.2 linkc.451G>A p.Gly151Arg missense_variant Exon 3 of 4 NP_001341098.1
KCNJ5XM_011542810.4 linkc.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 Appris UniProt
KCNJ5ENST00000529694.6 linkc.451G>A p.Gly151Arg missense_variant Exon 2 of 3 1 NM_000890.5 ENSP00000433295.1 P48544
KCNJ5ENST00000338350.4 linkc.451G>A p.Gly151Arg missense_variant Exon 3 of 4 1 ENSP00000339960.4 P48544
KCNJ5ENST00000533599.1 linkc.451G>A p.Gly151Arg missense_variant Exon 1 of 2 1 ENSP00000434266.1 P48544

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
58
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

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
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
29
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
D
LIST_S2
Uncertain
0.88
.;.;D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
1.0
D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.0
H;H;H
PhyloP100
10
PrimateAI
Pathogenic
0.89
D
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
D
GERP RS
5.5
Varity_R
0.96
gMVP
1.0
Mutation Taster
=1/99
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386352319; hg19: chr11-128781619; COSMIC: COSV57962649; API