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UniProtKB/Swiss-Prot P51795: Variant p.Glu527Asp

H(+)/Cl(-) exchange transporter 5
Gene: CLCN5
Variant information

Variant position:  527
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Glutamate (E) to Aspartate (D) at position 527 (E527D, p.Glu527Asp).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Similar physico-chemical property. Both residues are medium size and acidic.
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  2
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Nephrolithiasis 2 (NPHL2) [MIM:300009]: An X-linked recessive renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. Nephrolithiasis type 2 patients manifest hypercalciuria, hypophosphatemia, aminoaciduria, nephrocalcinosis and nephrolithiasis, renal insufficiency leading to renal failure in adulthood, rickets (33% of patients) and osteomalacia. {ECO:0000269|PubMed:15086899, ECO:0000269|PubMed:16247550, ECO:0000269|PubMed:16416111, ECO:0000269|PubMed:16822791, ECO:0000269|PubMed:17262170, ECO:0000269|PubMed:18025833, ECO:0000269|PubMed:19019917, ECO:0000269|PubMed:19657328, ECO:0000269|PubMed:21305656, ECO:0000269|PubMed:8559248, ECO:0000269|PubMed:9187673, ECO:0000269|PubMed:9259268, ECO:0000269|PubMed:9602200, ECO:0000269|PubMed:9853249}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In NPHL2; abolishes the chloride currents; total loss of function.
Any additional useful information about the variant.



Sequence information

Variant position:  527
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  746
The length of the canonical sequence.

Location on the sequence:   AAACLGGVTRMTVSLVVIMF  E LTGGLEYIVPLMAAAMTSKW
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         AAACLGGVTRMTVSLVVIMFELTGGLEYIVPLMAAAMTSKW

Mouse                         AAACLGGVTRMTVSLVVIMFELTGGLEYIVPLMAAAMTSKW

Rat                           AAACLGGVTRMTVSLVVIMFELTGGLEYIVPLMAAAMTSKW

Pig                           AAACLGGVTRMTVSLVVIMFELTGGLEYIVPLMAAAMTSKW

Rabbit                        AAACLGGVTRMTVSLVVIMFELTGGLEYIVPLMAAAMTSKW

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 746 H(+)/Cl(-) exchange transporter 5
Intramembrane 518 – 529 Helical


Literature citations

Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders.
Lloyd S.E.; Guenther W.; Pearce S.H.S.; Thomson A.; Bianchi M.L.; Bosio M.; Craig I.W.; Fisher S.E.; Scheinman S.J.; Wrong O.; Jentsch T.J.; Thakker R.V.;
Hum. Mol. Genet. 6:1233-1239(1997)
Cited for: VARIANTS NPHL2 HIS-30 INS; VAL-57; ARG-512 AND ASP-527;

Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure.
Smith A.J.; Reed A.A.; Loh N.Y.; Thakker R.V.; Lippiat J.D.;
Am. J. Physiol. 296:F390-F397(2009)
Cited for: CHARACTERIZATION OF VARIANTS NPHL2 VAL-57; ARG-270; GLU-513; TRP-516 AND ASP-527; CHARACTERIZATION OF VARIANTS LMWPHN PRO-280 AND LYS-524; SUBCELLULAR LOCATION;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.