Submissions for variant NM_000093.5(COL5A1):c.2897del (p.Pro966fs)

dbSNP: rs1179967153

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002233961	SCV000755910	pathogenic	Ehlers-Danlos syndrome, classic type, 1	2017-08-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro966Leufs*108) in the COL5A1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL5A1-related disease. Loss-of-function variants in COL5A1 are known to be pathogenic (PMID: 23587214). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001544703	SCV001763881	pathogenic	not provided	2019-04-22	criteria provided, single submitter	clinical testing	Has not been previously reported as pathogenic or benign to our knowledge; Reported in ClinVar as pathogenic (ClinVar Variant ID# 529237; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Many other frameshift variants in COL5A1 have been reported in HGMD in association with EDS (Stenson et al., 2014)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330852	SCV004038379	pathogenic	Ehlers-Danlos syndrome	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: COL5A1 c.2897delC (p.Pro966LeufsX108) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250906 control chromosomes (gnomAD). c.2897delC has been reported in the literature in at least one individual affected with Ehlers-Danlos Syndrome (e.g., Lavanya_2021). These data suggest the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 35396906). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.