Submissions for variant NM_016277.5(RAB23):c.481+4A>C

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002904881	SCV003261319	uncertain significance	Carpenter syndrome	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the RAB23 gene. It does not directly change the encoded amino acid sequence of the RAB23 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs747225405, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RAB23-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002904880	SCV003562231	uncertain significance	Inborn genetic diseases	2021-12-21	criteria provided, single submitter	clinical testing	The c.481+4A>C intronic alteration consists of a A to C substitution nucleotides after coding exon 4 in the RAB23 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004744478	SCV005351063	uncertain significance	RAB23-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The RAB23 c.481+4A>C variant is predicted to interfere with splicing. This variant is predicted to cause a minor splicing defect at the consensus splice site based on splicing prediction programs (Alamut Visual Plus v1.6.1; Splice AI, Jaganathan et al. 2019. PubMed ID: 30661751). However, the use of computer prediction software is not equivalent to functional evidence. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. Of note, a c.481G>C variant which is also predicted to impact the same consensus splice site, has been reported in the homozygous state in a patient with Carpenter Syndrome and functional studies showed aberrant splicing with exon 6 skipping and premature protein termination (Haye et al. 2014. PubMed ID: 25168863). At this time, the clinical significance of the c.481+4A>C variant is uncertain due to the absence of conclusive functional and genetic evidence.