Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003768960 | SCV001221151 | pathogenic | Ocular cystinosis; Juvenile nephropathic cystinosis; Inborn genetic diseases | 2019-11-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CTNS are known to be pathogenic (PMID: 9537412, 27102039). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with cystinosis (PMID: 12204010). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the CTNS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001585957 | SCV001821269 | likely pathogenic | Cystinosis | 2021-08-15 | criteria provided, single submitter | clinical testing | Variant summary: CTNS c.61_61+2delGGT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. Three predict the variant strengthens an alternate cryptic exonic 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251378 control chromosomes. c.61_61+2delGGT has been reported in the literature in at-least two individuals affected with Cystinosis and has been subsequently cited by others (example, Kiehntopf_2002, Rohayem_2019, David_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV003467783 | SCV004215231 | pathogenic | Nephropathic cystinosis | 2021-11-11 | criteria provided, single submitter | clinical testing |