ClinVar Miner

Submissions for variant NM_000539.3(RHO):c.563G>A (p.Gly188Glu) (rs1424131846)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001281 SCV001158457 likely pathogenic not specified 2019-06-03 criteria provided, single submitter clinical testing The RHO c.563G>A, p.Gly188Glu variant (rs1424131846) is reported in the medical literature in individuals and families with autosomal dominant retinitis pigmentosa (Macke 2014, Van Cauwenbergh 2017) and reportedly occurs de novo in one individual (Stone 2017). Additionally, another variant in the same codon, c.562G>A; p.Gly188Arg, is reported in several additional families with autosomal dominant retinitis pigmentosa (Dryja 1991, Martin-Merida 2018, Wang 2014) and displays altered functional properties including improper cellular localization and oligomerization (Gragg 2018). The c.563G>A, p.Gly188Glu variant is reported in the general population with an overall allele frequency of 0.0004% (1/246228 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The amino acid at this position is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Gragg M and Park PS. Misfolded rhodopsin mutants display variable aggregation properties. Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):2938-2948 Macke JP et al. Identification of novel rhodopsin mutations responsible for retinitis pigmentosa: implications for the structure and function of rhodopsin. Am J Hum Genet. 1993 Jul;53(1):80-9. Martin-Merida I et al. Toward the Mutational Landscape of Autosomal Dominant Retinitis Pigmentosa: A Comprehensive Analysis of 258 Spanish Families. Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2345-2354. Stone EM et al. Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology. 2017 Sep;124(9):1314-1331. Van Cauwenbergh C et al. Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families. PLoS One. 2017 Jan 11;12(1):e0170038.
Invitae RCV001041691 SCV001205320 pathogenic not provided 2020-01-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 188 of the RHO protein (p.Gly188Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 8317502, 28076437, 28559085). In at least one individual the variant was observed to be de novo. This variant has been reported to affect RHO protein function (PMID: 8253795). For these reasons, this variant has been classified as Pathogenic.
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV001265198 SCV001443234 likely pathogenic Retinitis pigmentosa 4 2020-09-01 criteria provided, single submitter clinical testing

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