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NM_017415.3(KLHL3):c.1583G>A (p.Arg528His) AND Pseudohypoaldosteronism type 2D

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 23, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000023475.4

Allele description [Variation Report for NM_017415.3(KLHL3):c.1583G>A (p.Arg528His)]

NM_017415.3(KLHL3):c.1583G>A (p.Arg528His)

Gene:
KLHL3:kelch like family member 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q31.2
Genomic location:
Preferred name:
NM_017415.3(KLHL3):c.1583G>A (p.Arg528His)
HGVS:
  • NC_000005.10:g.137628305C>T
  • NG_032569.1:g.112786G>A
  • NM_001257194.1:c.1487G>A
  • NM_001257195.2:c.1337G>A
  • NM_017415.3:c.1583G>AMANE SELECT
  • NP_001244123.1:p.Arg496His
  • NP_001244124.1:p.Arg446His
  • NP_059111.2:p.Arg528His
  • NC_000005.9:g.136963994C>T
  • NP_059111.2:p.R528H
  • Q9UH77:p.Arg528His
Protein change:
R446H; ARG528HIS
Links:
UniProtKB: Q9UH77#VAR_067528; OMIM: 605775.0004; dbSNP: rs199469636
NCBI 1000 Genomes Browser:
rs199469636
Molecular consequence:
  • NM_001257194.1:c.1487G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001257195.2:c.1337G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_017415.3:c.1583G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Pseudohypoaldosteronism type 2D (PHA2D)
Synonyms:
FAMILIAL HYPERKALEMIC HYPERTENSION; PSEUDOHYPOALDOSTERONISM, TYPE IID, AUTOSOMAL DOMINANT OR RECESSIVE
Identifiers:
MONDO: MONDO:0013781; MedGen: C3469605; Orphanet: 300525; Orphanet: 757; OMIM: 614495

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000044766OMIM
no assertion criteria provided
Pathogenic
(Oct 1, 2014) 		germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

SCV002776832Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Aug 23, 2021) 		unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, Semmekrot BA, Poujol A, Välimäki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, et al.

Nature. 2012 Jan 22;482(7383):98-102. doi: 10.1038/nature10814.

PubMed [citation]
PMID:
22266938
PMCID:
PMC3278668

KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.

Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, Mandet C, Broux F, Chabre O, Delahousse M, Esnault V, Fiquet B, Houillier P, Bagnis CI, Koenig J, Konrad M, et al.

Nat Genet. 2012 Mar 11;44(4):456-60, S1-3. doi: 10.1038/ng.2218. Erratum in: Nat Genet. 2012;44(5):609.

PubMed [citation]
PMID:
22406640
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000044766.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In 2 families segregating autosomal dominant pseudohypoaldosteronism type IID (PHA2D; 614495), Boyden et al. (2012) identified a G-to-A transition in the KLHL3 gene resulting in an arg-to-his substitution at codon 528 (R528H).

In 3 French families with hyperkalemic hypertension (PHAII), Louis-Dit-Picard et al. (2012) identified heterozygosity for a 1583G-A transition in the KLHL3 gene, resulting in the R528H substitution, located at a conserved residue in the V-VI interblade d-a loop that was predicted to interact with N529 (see 605775.0011). The mutation segregated with disease in each family and was not found in 800 normotensive controls.

Using transgenic mice expressing human KLHL3 with the R528H mutation, Susa et al. (2014) presented evidence that R528H causes PHA2D by interfering with KLHL3-dependent binding and degradation of the kinases WNK1 (605232) and WNK4 (601844), leading to excessive phosphorylation and activation of sodium channels, such as ENaC (see 600228), and sodium-chloride channels, such as NCC (SLC12A3; 600968), in distal convoluted tubules.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics, Fulgent Genetics, SCV002776832.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024