ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1496T>C (p.Ile499Thr)

gnomAD frequency: 0.00001  dbSNP: rs1001748912
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000556814 SCV000631626 uncertain significance Ehlers-Danlos syndrome, type 4 2023-12-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 499 of the COL3A1 protein (p.Ile499Thr). This variant is not present in population databases (gnomAD no frequency). 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: 459764). 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 RCV001176124 SCV001339991 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-02-28 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 499 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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 RCV001176124 SCV002702022 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-03-21 criteria provided, single submitter clinical testing The p.I499T variant (also known as c.1496T>C), located in coding exon 21 of the COL3A1 gene, results from a T to C substitution at nucleotide position 1496. The isoleucine at codon 499 is replaced by threonine, an amino acid with similar properties. 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.
Fulgent Genetics, Fulgent Genetics RCV002506307 SCV002814508 uncertain significance Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome 2021-08-31 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000556814 SCV004832457 uncertain significance Ehlers-Danlos syndrome, type 4 2024-09-11 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 499 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.

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