Submissions for variant NM_145200.5(CABP4):c.757C>T (p.Arg253Ter)

gnomAD frequency: 0.00001  dbSNP: rs761991624

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001075323	SCV001240941	likely pathogenic	Retinal dystrophy	2018-02-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001226380	SCV001398692	likely pathogenic	not provided	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg253*) in the CABP4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the CABP4 protein. This variant is present in population databases (rs761991624, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with CABP4-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 812242). This variant disrupts a region of the CABP4 protein in which other variant(s) (p.Asn258Ile) have been observed in individuals with CABP4-related conditions (PMID: 30718709). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526060	SCV005039971	uncertain significance	not specified	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: CABP4 c.757C>T (p.Arg253X) results in a premature termination codon, predicted to cause a truncation of the encoded protein but is not expected to result in nonsense mediated decay. The variant allele was found at a frequency of 8e-06 in 251312 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.757C>T has been reported in the literature in a family affected with cone-rod dystrophy without case level information (Sharon_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No variants downstream of the this position are classified as pathogenic. The following publication has been ascertained in the context of this evaluation (PMID: 31456290). ClinVar contains an entry for this variant (Variation ID: 812242). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV002267750	SCV001160944	pathogenic	Cone-rod dystrophy	2019-06-23	no assertion criteria provided	research