Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002229088 | SCV000631574 | pathogenic | Ehlers-Danlos syndrome, classic type, 1 | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change affects codon 659 of the COL5A2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL5A2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of COL5A2-related Ehlers-Danlos syndrome (PMID: 31517854, 33834621). In at least one individual the variant was observed to be de novo. This variant is also known as c.1997G>A. ClinVar contains an entry for this variant (Variation ID: 213101). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 29, but is expected to preserve the integrity of the reading-frame (PMID: 33834621). For these reasons, this variant has been classified as Pathogenic. |
| Center for Genomics, |
RCV000549387 | SCV003920876 | pathogenic | Ehlers-Danlos syndrome, classic type | 2024-05-10 | criteria provided, single submitter | clinical testing | This variant has been reported in the literature in at least 3 individuals with suspicion or clinical diagnoses of Ehlers-Danlos syndrome, classic type (cEDS), including as de novo in two families (Ritelli 2013 PMID: 23587214; Xu 2019 PMID: 31517854; Ma 2021 PMID: 33834621). It is not present in gnomAD, and has been submitted to ClinVar (Variation ID: 213101). Of note, this is a synonnymous variant that does not change the amino acid at this codon; however, it is located at the last nucleotide of exon 29 and computational splice prediction algorithms predict that it may weaken or abolish the donor splice site. An evaluation of this variant by cDNA sequencing from fibroblast-derived RNA supports these predictions, demonstrating that this variant results in the skipping of exon 29 (Ma 2021 PMID: 33834621). This is not expected to disrupt the reading frame but would remove 6 Gly-X-Y repeats in the encoded triple helical region which may impair the formation of type V collagen heterotrimers (Malfait 2024 PMID: 20301422). In summary, this variant is classified as pathogenic. |