Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001009030 | SCV001168840 | likely pathogenic | not provided | 2018-09-21 | criteria provided, single submitter | clinical testing | Although the c.3765delC likely pathogenic variant in the COL1A2 gene has not been reported to our knowledge, and has not been observed in large population cohorts (Lek et al., 2016). The c.3765delC variant causes a shift in reading frame starting at codon Phenylalanine 1256, changing it to a Serine, and creating a premature stop codon at position 31 of the new reading frame, denoted p.Phe1256SerfsX31. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Biallelic loss-of-function variants in the COL1A2 gene have been reported in association with autosomal recessive cardiovalvular EDS (cvEDS) (Schwarze et al., 2004; Malfait et al., 2006). In at least one reported family, the heterozygous parents were reported to be clinically unaffected (Malfait et al., 2006). Though other nonsense and frameshift variants in the COL1A2 gene have been reported in association with autosomal dominant osteogenesis imperfecta (Stenson et al., 2014), most of those variants are predicted to escape nonsense-mediated mRNA decay and result in an abnormal truncated protein. Thus, the clinical significance of the c.3765delC variant in the heterozygous state remains to be definitely determined, and the identification of this variant in additional affected heterozygous individuals may assist in further clarifying the role of this variant in autosomal dominant disease.In summary, c.3765delC in the COL1A2 gene is interpreted as a likely pathogenic variant. This variant may contribute to this individual's phenotype; however, we cannot exclude the possibility that it may represent carrier status for autosomal recessive cvEDS. A second potentially pathogenic variant, as would be expected with autosomal recessive inheritance, was not detected by sequence and deletion/duplication analysis of the COL1A2 gene. Therefore, clinical findings must also be considered in the diagnosis of this patient. The possibility this individual harbors a second sequence variant, or an exon-level deletion/duplication that is undetectable by this test, cannot be excluded. |