Submissions for variant NM_000090.4(COL3A1):c.560C>T (p.Thr187Ile)

gnomAD frequency: 0.00017  dbSNP: rs371583734

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586266	SCV000233345	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Reported in a patient with Marfan syndrome who presented with pneumomediastinum, craniofacial, musculoskeletal, and dermal features in published literature (Wooderchuck-Donahue et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 25944730)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586266	SCV000695377	benign	not provided	2017-07-10	criteria provided, single submitter	clinical testing
Invitae	RCV000698663	SCV000827343	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 187 of the COL3A1 protein (p.Thr187Ile). This variant is present in population databases (rs371583734, gnomAD 0.05%). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 25944730). ClinVar contains an entry for this variant (Variation ID: 199711). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001190472	SCV001357972	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 187 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 25944730). This variant has been identified in 12/282348 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Ambry Genetics	RCV001190472	SCV002651441	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-05-04	criteria provided, single submitter	clinical testing	The p.T187I variant (also known as c.560C>T), located in coding exon 6 of the COL3A1 gene, results from a C to T substitution at nucleotide position 560. The threonine at codon 187 is replaced by isoleucine, an amino acid with similar properties. This variant was detected in one individual from an aortopathy genetic testing cohort, who reportedly had a clinical diagnosis of Marfan syndrome (Wooderchak-Donahue W et al. Am J Med Genet A, 2015 Aug;167A:1747-57). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000586266	SCV003828129	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398906	SCV004120571	uncertain significance	COL3A1-related condition	2023-12-08	criteria provided, single submitter	clinical testing	The COL3A1 c.560C>T variant is predicted to result in the amino acid substitution p.Thr187Ile. This variant was reported as uncertain significance in an individual with Marfan syndrome (case #164, Wooderchak-Donahue et al. 2015. PubMed ID: 25944730). This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.