Submissions for variant NM_000090.4(COL3A1):c.812G>A (p.Arg271Gln)

gnomAD frequency: 0.00176  dbSNP: rs112185887

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000514955	SCV000233349	likely benign	not provided	2021-03-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27153395, 21086191, 25637381, 25525159, 24055113, 25758994, 26017485, 26332594, 25834947, 25985138, 25504618, 30122538, 28567303)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148458	SCV000283468	likely benign	Ehlers-Danlos syndrome, type 4	2024-01-31	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000148458	SCV000296869	benign	Ehlers-Danlos syndrome, type 4	2015-11-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000769564	SCV000317901	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-11-05	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.
Illumina Laboratory Services, Illumina	RCV000148458	SCV000425505	likely benign	Ehlers-Danlos syndrome, type 4	2018-03-15	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514955	SCV000603146	benign	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514955	SCV000610622	likely benign	not provided	2017-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181073	SCV000695380	benign	not specified	2019-04-01	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.812G>A (p.Arg271Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 278388 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1920 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant has been reported in patients with traumatic subarachnoid hemorrhage, familial abdominal aortic aneurysm and in two patients with clinical features of EhlersDanlos syndrome (Pickup _2011, van de Luijtgaarden_2015, Frank_2015). These reports however, do not provide unequivocal conclusions about association of the variant with Aortopathy. In a recent study examining a cohort of cases received to interpret variants originally identified by an outside laboratory, this variant was reportedly identified with another (identity not provided) mutation in 5 out of 14 unrelated probands, was inherited from an unaffected parent in one case and was reportedly found to have a normal type III collagen analysis in one patient (Pepin_2015). To our knowledge, no other experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (X2)/likely benign (X7). Based on the evidence outlined above, the variant was classified as benign.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680499	SCV000807882	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000181073	SCV000854894	likely benign	not specified	2017-08-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769564	SCV000900961	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2016-06-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769564	SCV000910959	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514955	SCV001371402	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	COL3A1: BP4, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277292	SCV002565660	benign	Ehlers-Danlos syndrome	2022-03-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505133	SCV002811809	likely benign	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2022-04-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000148458	SCV004831356	likely benign	Ehlers-Danlos syndrome, type 4	2024-02-05	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148458	SCV000190157	likely benign	Ehlers-Danlos syndrome, type 4	2014-06-01	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000148458	SCV000606896	not provided	Ehlers-Danlos syndrome, type 4		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000514955	SCV001797897	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000514955	SCV001808298	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000514955	SCV001929962	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000514955	SCV001963904	likely benign	not provided		no assertion criteria provided	clinical testing