ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.4087C>T (p.Arg1363Ter)

dbSNP: rs794728060
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181123 SCV000233399 pathogenic not provided 2016-08-10 criteria provided, single submitter clinical testing TheR1363X variant in the COL3A1 gene has not been reported previously as a disease-causing variant nor as a benign polymorphism, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1363X 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 R1363X variant is interpreted as a disease-causing variant
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709719 SCV000839947 likely pathogenic Ehlers-Danlos syndrome, type 4 2017-04-12 criteria provided, single submitter clinical testing The c.4087C>T (p.Arg1363*) variant has not been detected in our patients database nor has been seen in the ExAC population database. However, this variant was reported in Clinvar (submission accession # SCV000233399.7) as pathogenic by Genedx. No patient information was available for this Clinvar entry. This variant is predicted to create a non sense variant and a premature stop codon at amino acid position 1363 of the COL3A1 protein. This variant is thus predicted to result in a loss of function of the protein. Loss of function variants have reduced penetrance compared to missense and splicing variants, and studies have shown that the phenotype seems to be limited almost entirely to vascular events [PMID 21637106]. This variant is thus classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000709719 SCV000931283 pathogenic Ehlers-Danlos syndrome, type 4 2022-03-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 199753). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1363*) 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).
Baylor Genetics RCV000709719 SCV003836116 likely pathogenic Ehlers-Danlos syndrome, type 4 2022-01-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479047 SCV004223338 pathogenic Familial aortopathy 2023-11-06 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.4087C>T (p.Arg1363X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251148 control chromosomes. To our knowledge, no occurrence of c.4087C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000181123 SCV004226739 pathogenic not provided 2022-06-07 criteria provided, single submitter clinical testing PM2, PVS1
Ambry Genetics RCV004821996 SCV005568908 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2024-07-16 criteria provided, single submitter clinical testing The p.R1363* pathogenic mutation (also known as c.4087C>T), located in coding exon 50 of the COL3A1 gene, results from a C to T substitution at nucleotide position 4087. This changes the amino acid from an arginine to a stop codon within coding exon 50. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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