ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.1744G>A (p.Gly582Ser) (rs121912923)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000616909 SCV000731209 pathogenic Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
Collagen Diagnostic Laboratory,University of Washington RCV000018765 SCV000120449 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing
GeneDx RCV000181088 SCV000233364 pathogenic not provided 2017-12-13 criteria provided, single submitter clinical testing The G582S variant in the COL3A1 gene has been reported previously in association with EDS type IV (Anderson et al., 1997; Pepin et al., 2000). The G582S variant (also described as G415S due to alternative nomenclature) was initially identified in a 28-year-old female with thin skin, arachnodactyly, a history of multiple aneurysms and vascular ruptures and decreased thermal stability of type III procollagen by in vitro studies (Anderson et al., 1997). The G582S variant was subsequently identified in two additional individuals noted to have arterial complications from EDS type IV (Pepin et al., 2000). This variant is a nonconservative amino acid substitution of a non-polar Glycine with a neutral, polar Serine at a residue that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G582S variant was not observed in approximately 6,000 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
OMIM RCV000018765 SCV000039048 pathogenic Ehlers-Danlos syndrome, type 4 2000-03-09 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000181088 SCV000280066 likely pathogenic not provided 2011-08-15 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below we would classify this variant as a likely pathogenic variant. Variants that alter the sequence in the triple-helical domain of the COL3A1 gene result in EDS type IV (Schwarze, 2001). Two-thirds of identified disease-causing variants for EDS type IV result in single amino acid substitutions for glycine in the GLY-X-Y repeat of the triple helical region of the type III collagen molecule (GeneReviews). This p.Gly582Ser variant occurs in one of the triple helical region in which variants are known to cause EDS type IV. For example, Anderson et al (1997) reported a glycine to serine substitution at residue 415 in the triple helical region in a 28-year-old woman with thin skin, arachnodactyly, and a history of vascular ruptures. They concluded that this mutation causes a severe form of EDS type IV with multiple aneurisms and vascular ruptures. Pepin et al (2000) identified the underlying COL3A1 mutation in 135 patients with EDS type IV. In 85 of these patients, 73 different point mutations led to the substitution of some other amino acid for glycine throughout the triple-helical domain, one of which was the glycine to serine substitution at residue 415. Furthermore, they noted that this variant had been identified multiple times in unrelated index patients. Additionally, no control data is available. The variant is not in dbSNP or 1000 genomes (as of 25 May 2011).

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