Submissions for variant NM_002905.5(RDH5):c.285G>A (p.Trp95Ter)

gnomAD frequency: 0.00001  dbSNP: rs774122562

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190620	SCV000245656	pathogenic	Pigmentary retinal dystrophy	2014-12-30	criteria provided, single submitter	clinical testing	The Trp95X variant in RDH5 has been reported in 1 compound heterozygous Asian individual with fundus albipunctatus (Wang 2012). This variant has also been identified in 3/8708 of East Asian chromosomes by the Exome aggregation Consortium (http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 95, which is predicted to lead to a truncated or absent protein. Complete loss of RDH5 function is an established disease mechanism for fundus albipunctatus (Driessen 2001, Schatz 2010, Sergouniotis 2011). In summary, this variant meets our criteria to be classified as pathogenic for fundus albipunctatus in an autosomal recessive manner based on the predicted impact to the protein.
GeneDx	RCV000520865	SCV000617724	pathogenic	not provided	2017-08-28	criteria provided, single submitter	clinical testing	The W95X variant has been reported previously in association with fundus albipunctatus (Wang et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520865	SCV004294205	pathogenic	not provided	2022-10-30	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 208608). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with fundus albipunctatus (PMID: 22669287). This sequence change creates a premature translational stop signal (p.Trp95*) in the RDH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RDH5 are known to be pathogenic (PMID: 11675386, 22815624). This variant is present in population databases (rs774122562, gnomAD 0.04%).
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000190620	SCV005416659	pathogenic	Pigmentary retinal dystrophy		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting+PP4
GenomeConnect, ClinGen	RCV000844920	SCV000986732	not provided	Fundus albipunctatus, autosomal recessive		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 12/30/2014 by GTR ID 21766. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.