Submissions for variant NM_001845.6(COL4A1):c.781G>A (p.Gly261Ser)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003493352	SCV004241472	likely pathogenic	Brain small vessel disease 1 with or without ocular anomalies	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: COL4A1 c.781G>A (p.Gly261Ser) results in a non-conservative amino acid change located in the collagen triple helical region (Uniprot) of the encoded protein sequence. Alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. Four 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 14 and therefore can affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251422 control chromosomes (gnomAD). To our knowledge, no occurrence of c.781G>A in individuals affected with Porencephaly 1 and no experimental evidence demonstrating its impact on protein function have 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 likely pathogenic.