Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003112464 | SCV003787235 | pathogenic | not provided | 2021-12-27 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individual(s) with Alport syndrome (PMID: 2995919). This sequence change affects a donor splice site in intron 40 of the COL4A5 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Studies have shown that disruption of this splice site results in skipping of exon 40, but is expected to preserve the integrity of the reading-frame (PMID: 29959198). This variant disrupts the triple helix domain of COL4A5. 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 COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV004786872 | SCV005398377 | pathogenic | X-linked Alport syndrome | 2024-10-10 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, 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 X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly by glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). Exon skipping has been suggested but data was not shown (PMID: 29959198). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Other splice site variants comparable to the one identified in this case have strong previous evidence for pathogenicity. c.3604+1G>T and c.3604+2T>C have each been reported once as pathogenic (LOVD), c.3604+2T>A has been reported once as pathogenic (ClinVar) and in an individual with Alport syndrome (PMID: 12105244). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as pathogenic (ClinVar) and in an individual diagnosed with X-linked Alport syndrome (PMID: 29959198). (SP) 0905 - No published segregation 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 |