Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788295 | SCV005399489 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2023-07-16 | 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. Dominant-negative is due to missense variants affecting glycine residues in the Gly-X-Y repeat within the triple helical region (PMID: 29346445), while loss-of-function is due to null alleles. (I) 0108 - This gene is associated with both recessive and dominant disease. There is currently no genotype-phenotype correlation between autosomal dominant Ehlers-Danlos syndrome (EDS), vascular type (MIM#130050) and autosomal recessive polymicrogyria with or without vascular-type EDS (MIM#618343). (I) 0112 - The condition associated with this gene has incomplete penetrance. Specifically, in association with null alleles (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant inter and intra-familial variability has been reported for the same pathogenic variants (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies performed on total RNA extracted from this individual's fibroblasts demonstrated exon 44 skipping, leading to an in-frame deletion of 18 amino acids p.(Glu1068_Pro1085del) (Collagen Diagnostic Laboratory, University of Washington). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. However, the nucleotide is highly conserved. (I) 0601 - Variant affects the well-established functional triple helical domain. It leads to the in-frame deletion of the G-X-Y repeat. (SP) 0703 - Other splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. c.3255+5G>A and c.3255+1G>A have been reported in three individuals with vascular EDS; and functionally proven to lead to the same in-frame deletion of 18 amino acids p.(Glu1068_Pro1085del) (PMID: 9399899). (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) 1102 - Strong phenotype match for this individual. (SP) 1207 - Parental origin of the variant is unresolved. Subsequent analysis has shown that this variant is not maternally inherited; however, a sample from this individual's father has not been tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |