Submissions for variant NM_000090.4(COL3A1):c.1996G>A (p.Gly666Ser)

gnomAD frequency: 0.00002  dbSNP: rs755528878

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792990	SCV000932321	pathogenic	Ehlers-Danlos syndrome, type 4	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 666 of the COL3A1 protein (p.Gly666Ser). This variant is present in population databases (rs755528878, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of vascular Ehlers Danlos syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 640050). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL3A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL3A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002422679	SCV002717677	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-07-25	criteria provided, single submitter	clinical testing	The p.G666S variant (also known as c.1996G>A), located in coding exon 29 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1996. The glycine at codon 666 is replaced by serine, an amino acid with similar properties. The majority (approximately two-thirds) of COL3A1 mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (Pepin MG et al. Genet Med. 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 the COL3A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002501039	SCV002810958	likely pathogenic	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-11-06	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000792990	SCV004013335	likely pathogenic	Ehlers-Danlos syndrome, type 4	2023-06-27	criteria provided, single submitter	clinical testing	PM1, PM2, PM5_Supporting, PP2, PP3
All of Us Research Program, National Institutes of Health	RCV000792990	SCV004839080	likely pathogenic	Ehlers-Danlos syndrome, type 4	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 666 of the COL3A1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein. Although functional studies have not been performed for this variant, conserved glycine residues within the Gly-Xaa-Yaa repeats are required for the structural stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236) and missense variants occurring at these glycine residues have been associated with disease (PMID: 24922459, 25758994). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with vascular Ehlers-Danlos syndrome (PMID: 36977837), and in another individual affected with sporadic aortic dissection (PMID: 27975164). This variant has been identified in 4/251156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant affecting the same codon, p.Gly666Asp, has also been observed in individuals affected with vascular Ehlers-Danlos syndrome (PMID: 10706896). Based on the available evidence, this variant is classified as Likely Pathogenic.
Baylor Genetics	RCV000792990	SCV005049734	likely pathogenic	Ehlers-Danlos syndrome, type 4	2024-02-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000792990	SCV005884760	likely pathogenic	Ehlers-Danlos syndrome, type 4	2024-12-06	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.1996G>A (p.Gly666Ser) results in a non-conservative amino acid change in the encoded protein sequence. Alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-06 in 1613842 control chromosomes, predominantly at a frequency of 9.3e-06 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in COL3A1 causing Ehlers-Danlos syndrome, type 4 (7.4e-06 vs 0.0001), allowing no conclusion about variant significance. c.1996G>A has been reported in the presumed heterozygous state in the literature in individuals affected with sporadic aortic dissection or presumptive vascular Ehlers-Danlos syndrome (example, Bowen_2023, Li_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36977837, 27975164). ClinVar contains an entry for this variant (Variation ID: 640050). Based on the evidence outlined above, the variant was classified as likely pathogenic.