Submissions for variant NM_000090.4(COL3A1):c.3325C>T (p.Arg1109Ter)

dbSNP: rs112371422

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000087665	SCV000631659	pathogenic	Ehlers-Danlos syndrome, type 4	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1109*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of vascular Ehlers-Danlos syndrome (PMID: 24922459). ClinVar contains an entry for this variant (Variation ID: 101427). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001189408	SCV000738519	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2017-04-17	criteria provided, single submitter	clinical testing	The p.R1109* pathogenic mutation (also known as c.3325C>T), located in coding exon 45 of the COL3A1 gene, results from a C to T substitution at nucleotide position 3325. This changes the amino acid from an arginine to a stop codon within coding exon 45. This mutation was reported in an Ehlers-Danlos syndrome type IV cohort (Pepin MG et al. Genet Med. 2014;16(12):881-8). In addition to the clinical data presented in the literature, 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.
Color Diagnostics, LLC DBA Color Health	RCV001189408	SCV001356694	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-09-27	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 45 of the COL3A1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a few unrelated individuals affected with vascular Ehlers-Danlos syndrome (PMID: 24922459, 35092149, 35699227). 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 available evidence, this variant is classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269682	SCV001449849	likely pathogenic	not provided	2016-10-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001269682	SCV002820799	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	Identified in patients with vascular Ehlers-Danlos syndrome in the published literature (PMID: 24922459, 35092149); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33726816, 24922459, 35092149)
Mayo Clinic Laboratories, Mayo Clinic	RCV001269682	SCV004226738	pathogenic	not provided	2022-08-03	criteria provided, single submitter	clinical testing	PM2_supporting, PS4_moderate, PVS1
All of Us Research Program, National Institutes of Health	RCV000087665	SCV004829561	pathogenic	Ehlers-Danlos syndrome, type 4	2023-11-20	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 45 of the COL3A1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in a few unrelated individuals affected with vascular Ehlers-Danlos syndrome (PMID: 24922459, 35092149, 35699227). 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 available evidence, this variant is classified as Pathogenic.
Collagen Diagnostic Laboratory, University of Washington	RCV000087665	SCV000120557	pathogenic	Ehlers-Danlos syndrome, type 4		no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000087665	SCV004022199	pathogenic	Ehlers-Danlos syndrome, type 4	2023-07-21	no assertion criteria provided	research	The variant NM_000090.4:c.3325C>T (chr2:189007569) in COL3A1 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2, PP5) this variant classifies as pathogenic.