Submissions for variant NM_000554.6(CRX):c.292C>T (p.Arg98Ter)

dbSNP: rs751018117

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Genetics Laboratory, West China Hospital, Sichuan University	RCV001256189	SCV001423822	pathogenic	Retinitis pigmentosa		criteria provided, single submitter	in vitro	A heterozygous nonsense variant c.292C > T (p.R98X) of CRX gene was identified to be present in the affected male with autosomal dominant inherited Retinitis pigmentosa.The nonsense variant was supposed to result in a truncated CRX protein with a destroyed homedomain, which is essential for CRX translation. The in vitro expression assay showed that the potential truncated protein was not detected,indicating that the variant may cause a loss-of-function mutation of CRX gene.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001879957	SCV002259694	pathogenic	Leber congenital amaurosis 7; Cone-rod dystrophy 2	2023-09-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CRX protein in which other variant(s) (p.Tyr258*) have been determined to be pathogenic (PMID: 22968130, 25270190). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this premature translational stop signal affects CRX function (PMID: 30460480). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 978221). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 30460480). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg98*) in the CRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 202 amino acid(s) of the CRX protein.
SingHealth Duke-NUS Institute of Precision Medicine	RCV005235552	SCV005881666	likely pathogenic	Cone-rod dystrophy 2	2025-02-05	criteria provided, single submitter	clinical testing	Null variant is predicted to remove more than 10% of protein in a gene where LOF is a known mechanism for pathogenicity (PVS1). Variant allele frequency is below 0.000001 in gnomAD exomes and not found in genomes (PM2)