Submissions for variant NM_000393.5(COL5A2):c.162G>T (p.Trp54Cys)

dbSNP: rs863223500

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195689	SCV000249996	uncertain significance	not provided	2012-11-29	criteria provided, single submitter	clinical testing	TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. Approximately 4% of patients with autosomal dominant Ehlers-Danlos syndrome, classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011).p.Trp54Cys (TGG>TGT): c.162 G>T in exon 2 of the COL5A2 gene (NM_000393.3)The Trp54Cys variant in the COL5A2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Trp54Cys results in a non-conservative amino acid substitution of a non-polar Tryptophan with a polar Cysteine at a position that is conserved across species. In silico analysis predicts Trp54Cys is probably damaging to the protein structure/function. The NHLBI ESP Exome Variant Server reports Trp54Cys was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with Ehlers Danlos syndrome, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Trp54Cys is a disease-causing mutation or a rare benign variant. This variant was found in TAAD.
PreventionGenetics, part of Exact Sciences	RCV003407698	SCV004111051	uncertain significance	COL5A2-related condition	2023-03-27	criteria provided, single submitter	clinical testing	The COL5A2 c.162G>T variant is predicted to result in the amino acid substitution p.Trp54Cys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Invitae	RCV003758720	SCV004408830	uncertain significance	Ehlers-Danlos syndrome, classic type, 1	2022-11-23	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 213133). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 54 of the COL5A2 protein (p.Trp54Cys).