NM_002900.2(RBP3):c.3238G>A (p.Asp1080Asn)

NM_002900.2(RBP3):c.3238G>A (p.Asp1080Asn)

Variant type:
single nucleotide variant
Cytogenetic location:
10q11.2
Genomic location:
  • Chr10:47353508 (on Assembly GRCh38)
  • Chr10:48385854 (on Assembly GRCh37)
Protein change:
D1080N
HGVS:
  • NG_029718.1:g.10138G>A
  • NM_002900.2:c.3238G>A
  • NC_000010.11:g.47353508G>A
  • NC_000010.10:g.48385854C>T
  • NP_002891.1:p.Asp1080Asn
Links:
NCBI 1000 Genomes Browser:
rs146150511
Molecular consequence:
NM_002900.2:c.3238G>A: missense variant [Sequence Ontology SO:0001583]
Allele frequency:
GO-ESP 0.00008 (T)

Clinical significance

NM_002900.2(RBP3):c.3238G>A (p.Asp1080Asn)

Clinical significance:
Pathogenic/Likely pathogenic
Review status:
(1/4)1 star out of maximum of 4 stars
classified by single submitter
Number of submission(s):
1
Condition(s)
See supporting ClinVar records

1 Affected Gene

Recent Activity

Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter
(Last submitted)
Submission accession
Pathogenic
(May 16, 2013)
classified by single submitter
(literature only)
literature onlygermlinePubMed (2)
OMIM
(May 16, 2013)
SCV000067387

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermlinenot providednot provided

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

In 4 sibs from a consanguineous Italian family with retinitis pigmentosa (RP66; 615233), den Hollander et al. (2009) identified homozygosity for a c.3238G-A transition in exon 2 of the RBP3 gene, resulting in an asp1080-to-asn (D1080N) substitution at a highly conserved residue in the fourth IRBP repeat module. The mutation was not found in 116 Italian controls without known photoreceptor disease or 94 controls of mixed North American ancestry.
In transiently transfected mouse photoreceptor-derived cells, Li et al. (2013) demonstrated that the D1080N mutation abolishes secretion of RBP3, and immunoblot analysis revealed that the mutant RBP3 forms insoluble high molecular weight complexes via disulfide bonds. Confocal microscopy showed that the mutant protein was not transported to the Golgi apparatus, but accumulated in the endoplasmic reticulum. In addition, the D1080N mutant induced upregulation and nuclear translocation of CHOP (DDIT3; 126337), a proapoptotic transcription factor associated with the unfolded protein response. Chemical chaperones and low temperature significantly rescued the secretion of the mutant protein, suggesting that misfolding is the molecular basis for the pathogenicity of D1080N substitution.

Last Updated: Aug 5, 2014

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