Submissions for variant NM_000393.5(COL5A2):c.1401G>A (p.Pro467=)

dbSNP: rs1553515794

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657905	SCV000779670	likely pathogenic	not provided	2018-05-30	criteria provided, single submitter	clinical testing	The c.1401 G>A variant has been previously reported in an individual with classic Ehlers-Danlos syndrome (Symoens et al., 2012). published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1401 G>A variant is not observed in large population cohorts (Lek et al., 2016). Several in silico splice prediction models predict that c.1401 G>A may destroy the natural donor site and lead to abnormal gene splicing. Analysis of cDNA demonstrated that the c.1401 G>A variant results in an in-frame deletion of exon 21 (Symoens et al., 2012). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470943	SCV002767183	pathogenic	Ehlers-Danlos syndrome, classic type, 2	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with Ehlers-Danlos syndrome, classic type, 2 (EDS) (MIM#130010) (PMID: 23587214). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Sequencing of cDNA obtained from an EDS patient has proven skipping of exon 21, leading to an in-frame deletion (PMID: 22696272). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0601 - Variant affects the well-established functional G-X-Y triple helix (UCSC, PMID: 22696272). (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported in an EDS patient and classified as likely pathogenic by a diagnostic laboratory in ClinVar (PMID: 22696272). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional 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
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000657905	SCV004013435	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	PM2, PS4_supporting, PP3
Invitae	RCV003594012	SCV004293032	uncertain significance	Ehlers-Danlos syndrome, classic type, 1	2023-05-13	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 546102). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with Ehlers-Danlos syndrome, congenital scoliosis (PMID: 22696272, 32381727). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 467 of the COL5A2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL5A2 protein. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon.