Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003493328 | SCV004241122 | pathogenic | Brain small vessel disease 1 with or without ocular anomalies | 2023-12-15 | criteria provided, single submitter | clinical testing | Variant summary: COL4A1 c.2870G>C (p.Gly957Ala) results in a non-conservative amino acid change of a position 1 glycine in a Gly-X-Y motif in the collagen triple helix repeat (IPR008160) of the encoded protein sequence. Alterations of these critical position-1 glycine residues within the collagen triple-helix are common mechanisms of disease. Five of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the first nucleotide of exon 35 and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 3' acceptor site and two predict the variant weakens the same 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 1461810 control chromosomes (gnomAD v4). c.2870G>C has been observed in our lab as a de novo occurrence in at least one individual affected with Porencephaly. These data suggest the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |