Submissions for variant NM_000093.5(COL5A1):c.2722C>T (p.Pro908Ser)

gnomAD frequency: 0.00005  dbSNP: rs144985214

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002230750	SCV001211900	benign	Ehlers-Danlos syndrome, classic type, 1	2024-11-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001575732	SCV001802786	uncertain significance	not provided	2021-10-19	criteria provided, single submitter	clinical testing	Has been reported in a patient with clinical features of Ehlers-Danlos syndrome in published literature (Kratzsch et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (Symoens et al., 2013; Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 373260; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29578302, 26582918)
Ambry Genetics	RCV002429341	SCV002741460	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-05-25	criteria provided, single submitter	clinical testing	The p.P908S variant (also known as c.2722C>T), located in coding exon 33 of the COL5A1 gene, results from a C to T substitution at nucleotide position 2722. The proline at codon 908 is replaced by serine, an amino acid with similar properties. This variant has been detected in an individual with reported to have features consistent with classic Ehlers-Danlos syndrome (Kratzsch J et al. J Dtsch Dermatol Ges, 2018 Apr;16:504-507). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224270	SCV003919831	uncertain significance	Ehlers-Danlos syndrome, classic type, 1; Fibromuscular dysplasia, multifocal	2021-03-30	criteria provided, single submitter	clinical testing	COL5A1 NM_000093.4 exon 33 p.Pro908Ser (c.2722C>T): This variant has not been reported in the literature but is present in 0.006% (8/128742) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-137686949-C-T). This variant is present in ClinVar (Variation ID:373260). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV000414656	SCV000491840	uncertain significance	not specified	2016-11-17	flagged submission	clinical testing	A variant of uncertain significance has been identified in the COL5A1 gene. The P908S variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The P908S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with EDS (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.