Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788452 | SCV005397973 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2022-06-24 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with COL3A1-related disease. Missense variants affecting glycine residues of the Gly-X-Y triplet repeat within the triple helical region exert dominant-negative effects whilst variants resulting in protein termination codon lead to haploinsufficiency and a milder clinical course in patients with Ehlers-Danlos syndrome (EDS) (PMID: 25758994). Complete loss of function biallelic variants have been reported in patients with polymicrogyria with or without vascular-type EDS (PMID: 28742248). (I) 0108 - This gene is associated with both recessive and dominant disease: polymicrogyria with or without vascular-type EDS (MIM#618343) and Ehlers-Danlos syndrome, vascular type (MIM#130050), respectively (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Null alleles have been reported to have reduced penetrance and variable expressivity compared to missense variants and may confer milder disease with delayed onset (PMID: 21637106; 28742248). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity and have been reported in patients with COL3A1-related disease (ClinVar; PMID: 25758994). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |