Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV002012109 | SCV002223998 | uncertain significance | Ehlers-Danlos syndrome, type 4 | 2021-10-11 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with tyrosine at codon 38 of the COL3A1 protein (p.Ser38Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function. This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (ExAC no frequency). |
Johns Hopkins Genomics, |
RCV002012109 | SCV004024544 | uncertain significance | Ehlers-Danlos syndrome, type 4 | 2023-05-16 | criteria provided, single submitter | clinical testing | This COL3A1 missense variant (rs755509578) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 2/282350 total alleles; 0.0007%; no homozygotes). It has been reported in ClinVar (Variation ID 1448280), but has not been reported in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be tolerated, but these algorithms have low specificity, especially for predicting gain of function variants. The serine residue at this position is evolutionarily conserved across many species assessed, but several species have a different amino acid at this position5. We consider the clinical significance of c.113C>A;p.Ser38Tyr in COL3A1 to be uncertain at this time. |