Submissions for variant NM_000090.4(COL3A1):c.347T>G (p.Ile116Ser)

gnomAD frequency: 0.00007  dbSNP: rs769622439

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059153	SCV001223765	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 116 of the COL3A1 protein (p.Ile116Ser). 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: 854169). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is present in population databases (rs769622439, gnomAD 0.02%).
Color Diagnostics, LLC DBA Color Health	RCV001180915	SCV001345967	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 replaces isoleucine with serine at codon 116 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 5/244258 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.
GeneDx	RCV002473183	SCV002770299	uncertain significance	not provided	2022-12-20	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function
All of Us Research Program, National Institutes of Health	RCV001059153	SCV004832906	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-07-29	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces isoleucine with serine at codon 116 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 5/244258 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.