rs386352319

Variant names:

• chr11-128911724-G-A
• rs386352319
• NM_000890.5:c.451G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-128911724-G-A
• chr11-128911724-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-128911725-G-A is described in Lovd as [Pathogenic].
• 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	c.451G>A	p.Gly151Arg	missense_variant	Exon 2 of 3	ENST00000529694.6	NP_000881.3
KCNJ5	NM_001354169.2	c.451G>A	p.Gly151Arg	missense_variant	Exon 3 of 4		NP_001341098.1
KCNJ5	XM_011542810.4	c.451G>A	p.Gly151Arg	missense_variant	Exon 2 of 3		XP_011541112.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

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
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

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

LitVar

Other links and lift over

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