Submissions for variant NM_000093.5(COL5A1):c.4393-4_4398del

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	RCV003317695	SCV004020442	likely pathogenic	Ehlers-Danlos syndrome	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: COL5A1 c.4393-4_4398del10 spans a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site and four predict the variant creates a cryptic 3' acceptor site that is typically 10nt into exon 57, which is predicted to cause a frameshift. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251182 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4393-4_4398del10 in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.