NM_017415.3(KLHL3):c.1583G>A (p.Arg528His) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 23, 2022
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:: RCV002513190.3

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003439203	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 23, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25925082, 22266938, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003439203

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 23, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations.

Mayan H, Carmon V, Oleinikov K, London S, Halevy R, Holtzman EJ, Tenenbaum-Rakover Y, Farfel Z, Hanukoglu A.

Nephron. 2015;130(1):59-65. doi: 10.1159/000381563. Epub 2015 Apr 22.

PubMed [citation]

PMID:: 25925082

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439203.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 30518). This missense change has been observed in individuals with autosomal dominant pseudohypoaldosteronism type 2 (PMID: 22266938, 25925082). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 528 of the KLHL3 protein (p.Arg528His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg528 amino acid residue in KLHL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22266938). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt KLHL3 protein function.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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