Submissions for variant NM_000090.4(COL3A1):c.706C>T (p.Pro236Ser)

gnomAD frequency: 0.00001  dbSNP: rs771858477

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181071	SCV000233347	uncertain significance	not provided	2013-10-17	criteria provided, single submitter	clinical testing	Pro236Ser (CCC>TCC): c.706 C>T in exon 9 of the COL3A1 gene (NM_000090.3). The Pro236Ser variant in the COL3A1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro236Ser results in a non-conservative amino acid substitution of a non-polar Proline with a neutral, polar Serine at a position that is conserved in mammals. The Pro236Ser variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations in nearby residues have been reported in association with Ehlers-Danlos syndrome (EDS), however, the majority of disease-causing missense mutations in the COL3A1 gene are Glycine substitutions in the Gly-X-Y repeats. Also, in silico analysis predicts Pro236Ser is benign to the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if Pro236Ser is a disease-causing mutation or a rare benign variant. At least 95% of patients with autosomal dominant Ehlers-Danlos syndrome type IV have been reported to have a mutation in the COL3A1 gene (Pepin M et al., 2011). The variant is found in TAAD panel(s).
Ambry Genetics	RCV001185491	SCV000738514	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-02-15	criteria provided, single submitter	clinical testing	The p.P236S variant (also known as c.706C>T), located in coding exon 9 of the COL3A1 gene, results from a C to T substitution at nucleotide position 706. The proline at codon 236 is replaced by serine, an amino acid with some similar properties. This variant was previously reported in the SNPDatabase as rs771858477. Based on data from ExAC, the T allele has an overall frequency of <0.01% (3/105680). This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659413	SCV000781225	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001185491	SCV001351715	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 236 of the COL3A1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/250844 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001245344	SCV001418627	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 236 of the COL3A1 protein (p.Pro236Ser). This variant is present in population databases (rs771858477, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 199713). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function. 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.