Submissions for variant NM_004560.4(ROR2):c.1582C>T (p.Arg528Ter)

dbSNP: rs1448877786

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001942300	SCV002232727	pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ROR2 protein in which other variant(s) (p.Trp720*) have been determined to be pathogenic (PMID: 10932187). 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 create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with ROR2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg528*) in the ROR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 416 amino acid(s) of the ROR2 protein.
Neuberg Centre For Genomic Medicine, NCGM	RCV003444965	SCV004171278	likely pathogenic	Autosomal recessive Robinow syndrome		criteria provided, single submitter	clinical testing	The stop gain c.1582C>T (p.Arg528Ter) variant in ROR2 gene has been reported to the ClinVar database as Pathogenic. The c.1582C>T variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. The nucleotide change c.1582C>T in ROR2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. This variant is present in the last exon of the ROR2 gene, and hence, additional studies will be required to prove the pathogenicity of this variant. However, other pathogenic truncating variants [(c.2160G>A | p.Trp720Ter); (c.2249del | p.Gly750fs)], downstream to the above reported variants, have previously been reported (van Bokhoven et al. 2000; Lv et al. 2009). For these reasons, this variant has been classified as Likely Pathogenic.