Submissions for variant NM_000090.4(COL3A1):c.2002C>A (p.Pro668Thr)

dbSNP: rs1801183

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000514205	SCV000233368	benign	not provided	2019-06-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25525159, 8514866, 27153395, 25834947)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214945	SCV000268912	benign	not specified	2015-05-08	criteria provided, single submitter	clinical testing	p.Pro668Thr in exon 29 of COL3A1: This variant is not expected to have clinical significance it has been identified in 0.8% (129/16334) of South Asian chromosom es and 0.1% (71/66412) European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1801183). This variant has been r eported in one adult with abdominal aortic aneurysm and a nephew with an intracr anial aneurysm; however, the variant was also identifed in two unaffected, elder ly brothers (Tromp 1993).
PreventionGenetics, part of Exact Sciences	RCV000214945	SCV000302029	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000769568	SCV000319468	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-09-03	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000380172	SCV000425524	benign	Ehlers-Danlos syndrome, type 4	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000380172	SCV000554715	benign	Ehlers-Danlos syndrome, type 4	2024-01-31	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514205	SCV000609835	likely benign	not provided	2017-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000514205	SCV000695362	benign	not provided	2017-04-17	criteria provided, single submitter	clinical testing	Variant summary: The COL3A1 c.2002C>A (p.Pro668Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/5 in silico tools predict a damaging outcome for this variant, although the change still may be tolerated. This variant was found in the large control datasets of ExAC and gnomAD at a frequency of 0.00174 and 0.001629 (210/120672 and 451/276924 chrs tested, respectively), predominantly in South Asian individuals, including 5 homozygotes. The observed frequencies exceed the estimated maximal expected allele frequency of a pathogenic COL3A1 variant (0.0000013), indicating that the variant is a benign polymorphism. The variant of interest has been reported in several affected individuals via publications, but has failed to segregate with the disease (Tromp, 1993). Lastly, it has been classified as Benign/Likely Benign by multiple clinical diagnostic laboratories/reputable databases. Taking together, the variant is classified as Benign.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000380172	SCV000781235	uncertain significance	Ehlers-Danlos syndrome, type 4	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514205	SCV000883647	benign	not provided	2023-09-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769568	SCV000900965	benign	Familial thoracic aortic aneurysm and aortic dissection	2017-08-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769568	SCV000910958	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514205	SCV001153223	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	COL3A1: BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277438	SCV002565615	likely benign	Ehlers-Danlos syndrome	2021-12-20	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993864	SCV004812483	likely benign	Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2023-08-01	criteria provided, single submitter	clinical testing