Submissions for variant NM_000090.4(COL3A1):c.3793C>A (p.Leu1265Met)

gnomAD frequency: 0.00001  dbSNP: rs200052168

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002314221	SCV000738542	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-09-16	criteria provided, single submitter	clinical testing	The p.L1265M variant (also known as c.3793C>A), located in coding exon 48 of the COL3A1 gene, results from a C to A substitution at nucleotide position 3793. The leucine at codon 1265 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in a vascular genetic testing cohort (Hicks KL et al. J Vasc Surg, 2018 09;68:701-711). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001346564	SCV001540781	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1265 of the COL3A1 protein (p.Leu1265Met). This variant is present in population databases (rs200052168, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of COL3A1-related conditions (PMID: 29510914). ClinVar contains an entry for this variant (Variation ID: 519611). 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.
GeneDx	RCV001591386	SCV001814590	uncertain significance	not provided	2024-06-20	criteria provided, single submitter	clinical testing	Identified in a 41 year-old female with a ruptured Achilles tendon and no history of aortic or arterial disease in published literature; however, no segregation or functional studies were reported (PMID: 29510914); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); This variant is associated with the following publications: (PMID: 29510914)
Color Diagnostics, LLC DBA Color Health	RCV002314221	SCV004363044	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 1265 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having genetically triggered vascular disease (PMID: 29510914). This variant has been identified in 3/250658 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.
All of Us Research Program, National Institutes of Health	RCV001346564	SCV004827603	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 1265 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having genetically triggered vascular disease (PMID: 29510914). This variant has been identified in 3/250658 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.