ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.2489C>T (p.Pro830Leu)

gnomAD frequency: 0.00004  dbSNP: rs886038849
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001189412 SCV000318536 likely benign Familial thoracic aortic aneurysm and aortic dissection 2020-04-29 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000554446 SCV000631643 uncertain significance Ehlers-Danlos syndrome, type 4 2021-11-05 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 830 of the COL3A1 protein (p.Pro830Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 263573). 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.
Color Diagnostics, LLC DBA Color Health RCV001189412 SCV001356698 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-11-29 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 830 of the COL3A1 protein. Computational prediction tool indicates that this variant may have a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with acute Stanford type B aortic dissection (PMID: 33282382). This variant has been identified in 2/156726 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.
GeneDx RCV001582894 SCV001813292 uncertain significance not provided 2020-03-09 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002229709 SCV002512027 uncertain significance not specified 2024-07-15 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.2489C>T (p.Pro830Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 1551562 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL3A1 causing Polymicrogyria With Or Without Vascular-Type Ehlers-Danlos Syndrome, allowing no conclusion about variant significance. c.2489C>T has been reported in the literature in an individual affected with Acute Stanford type B aortic dissection, without strong evidence for causality (Erhart_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Polymicrogyria With Or Without Vascular-Type Ehlers-Danlos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33282382). ClinVar contains an entry for this variant (Variation ID: 263573). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health RCV000554446 SCV004833668 uncertain significance Ehlers-Danlos syndrome, type 4 2024-09-23 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 830 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 2/156726 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. Therefore, this variant is classified as a Variant of Uncertain Significance.

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