ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1961G>A (p.Gly654Glu)

dbSNP: rs587779620
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV002483171 SCV002789736 likely pathogenic Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome 2021-08-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV004821973 SCV005568888 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2024-10-17 criteria provided, single submitter clinical testing The p.G654E variant (also known as c.1961G>A), located in coding exon 28 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1961. The glycine at codon 654 is replaced by glutamic acid, an amino acid with similar properties. The majority (approximately two-thirds) ofCOL3A1mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (PepinMG et al.GenetMed.2014;16(12):881-8; Frank M et al.Eur J Hum Genet. 2015;23(12):1657-64). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif in theCOL3A1protein and inserts a bulky side chain into asterically-constrainedregion (Bella J et al.Science.1994;266:75-81;HohenesterE et al.Proc. Natl.Acad. Sci. U.S.A.2008;105:18273-7; Ambry internal data). This variant was reported in individuals with features consistent with vascular Ehlers-Danlos syndrome (EDS) (Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Butler MG et al. Genes (Basel), 2022 Feb;13:[ePub ahead of print]). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Collagen Diagnostic Laboratory, University of Washington RCV000087580 SCV000120470 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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