ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1714C>T (p.Arg572Ter)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003112138 SCV003786406 pathogenic Ehlers-Danlos syndrome, type 4 2023-11-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg572*) in the COL3A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL3A1 are known to be pathogenic (PMID: 24922459). This variant is present in population databases (rs572097661, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with vascular Ehlers-Danlos syndrome (PMID: 30474650, 31141158). ClinVar contains an entry for this variant (Variation ID: 2418894). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV003528437 SCV004362973 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-05-31 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 24 of the COL3A1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with vascular Ehlers-Danlos syndrome (PMID: 30474650, 31141158, 36977837). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of COL3A1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017969 SCV004847863 likely pathogenic Ehlers-Danlos syndrome 2019-10-11 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: The p.Arg572X variant in COL3A1 has not been previously reported in individuals with Ehlers-Danlos syndrome (EDS) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 572, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the COL3A1 gene is an established disease mechanism in Ehlers-Danlos syndrome and is associated with late-onset, reduced penetrance, and possibly a milder clinical course (Leistritz 2011, Frank 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant EDS. ACMG/AMP Criteria applied: PVS1, PM2.
Mayo Clinic Laboratories, Mayo Clinic RCV004790475 SCV005413542 pathogenic not provided 2023-12-21 criteria provided, single submitter clinical testing PM2, PM6, PS4_moderate, PVS1

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