Submissions for variant NM_000093.5(COL5A1):c.3398G>A (p.Arg1133Gln)

gnomAD frequency: 0.00005  dbSNP: rs759580799

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002231685	SCV000631493	benign	Ehlers-Danlos syndrome, classic type, 1	2023-09-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000542708	SCV000897501	uncertain significance	Ehlers-Danlos syndrome, classic type	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000999273	SCV001155823	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000999273	SCV001801068	uncertain significance	not provided	2019-02-25	criteria provided, single submitter	clinical testing	Located in the the triple-helical region, in the X position of Gly-X-Y repeat (Symoens et al., 2012; Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported as a variant of uncertain significance in ClinVar but additional evidence is not available (SCV000631493.1; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27975164)
PreventionGenetics, part of Exact Sciences	RCV003424097	SCV004117301	uncertain significance	COL5A1-related disorder	2023-08-10	criteria provided, single submitter	clinical testing	The COL5A1 c.3398G>A variant is predicted to result in the amino acid substitution p.Arg1133Gln. This variant was reported in an individual with Ehlers-Danlos syndrome (Table 2 in Junkiert-Czarnecka et al 2022. PubMed ID: 35723357) and in an individual with aortic dissection (Table 1 in Chen P et al 2021. PubMed ID: 34041919). This variant is reported in 0.027% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-137701060-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004609426	SCV005106044	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-05-24	criteria provided, single submitter	clinical testing	The p.R1133Q variant (also known as c.3398G>A), located in coding exon 43 of the COL5A1 gene, results from a G to A substitution at nucleotide position 3398. The arginine at codon 1133 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in association with aortic dissection and Ehlers-Danlos syndrome (Li Z et al. Sci China Life Sci, 2017 Jan;60:57-65; Chen P et al. J Am Heart Assoc, 2021 Jun;10:e019276; Junkiert-Czarnecka A et al. Curr Issues Mol Biol, 2022 Mar;44:1472-1478). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV002231685	SCV002547279	not provided	Ehlers-Danlos syndrome, classic type, 1		no assertion provided	literature only