Submissions for variant NM_000090.4(COL3A1):c.3440C>T (p.Pro1147Leu)

gnomAD frequency: 0.00001  dbSNP: rs889877870

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437527	SCV000534730	uncertain significance	not provided	2016-12-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the COL3A1 gene. The P1147L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This 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. The P1147L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, while the P1147L variant is located in a Gly-X-Y motif in the triple helical region of the COL3A1 gene, it does not affect a Glycine residue in this motif, as the majority of pathogenic missense variants do (Stenson et al., 2014; Symoens et al., 2012).
Color Diagnostics, LLC DBA Color Health	RCV000772009	SCV000904965	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-05	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the triple-helical region of the COL3A1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact 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 2/245792 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209279	SCV001380705	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-10-01	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 391619). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1147 of the COL3A1 protein (p.Pro1147Leu).
Ambry Genetics	RCV000772009	SCV002616929	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-07-26	criteria provided, single submitter	clinical testing	The p.P1147L variant (also known as c.3440C>T), located in coding exon 47 of the COL3A1 gene, results from a C to T substitution at nucleotide position 3440. The proline at codon 1147 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available 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 alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000772009	SCV004240468	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001209279	SCV005427375	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-07-10	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the triple-helical region of the COL3A1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact 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 2/245792 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.