Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000693892 | SCV000822314 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2018-07-31 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with cysteine at codon 1068 of the COL3A1 protein (p.Gly1068Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL3A1-related disease. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL3A1, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). A different missense substitution at this codon (p.Gly1068Val) has been reported in an individual affected with Ehlers-Danlos syndrome type IV (PMID: 24922459). 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. |
Human Genome Sequencing Center Clinical Lab, |
RCV000693892 | SCV001434882 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2019-12-30 | criteria provided, single submitter | clinical testing | This c.3202G>T variant in the COL3A1 gene results in the substitution of a glycine amino acid with a cysteine at codon 1068 of the encoded protein (p.Gly1068Cys). This glycine substitution lies within the Gly-X-Y repeat of the triple helical region of the type III procollagen molecule where the majority of identified pathogenic variants reside (PMID: 24922459, 25758994). This variant is not present in population databases (gnomAD). Multiple lines of computational evidence support a deleterious effect on the protein product. Though this variant has not been previously reported, a different missense change at the same amino acid position (p.Gly1068Val) has been reported in an individual affected with vascular Ehlers-Danlos syndrome (PMID: 24922459). Therefore, this variant is classified as likely pathogenic. |