Submissions for variant NM_000090.4(COL3A1):c.2805T>C (p.Pro935=)

gnomAD frequency: 0.00018  dbSNP: rs111567071

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000124412	SCV000167845	benign	not specified	2014-06-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV000313108	SCV000425534	benign	Ehlers-Danlos syndrome, type 4	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000313108	SCV000631652	likely benign	Ehlers-Danlos syndrome, type 4	2024-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000777801	SCV000738543	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2017-03-13	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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659423	SCV000781237	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755958	SCV000883643	likely benign	not provided	2017-07-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777801	SCV000913793	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-10-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000124412	SCV001372394	benign	not specified	2020-06-29	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.2805T>C alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 250242 control chromosomes (gnomAD). The observed variant frequency is approximately 93 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 benign. To our knowledge, no occurrence of c.2805T>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (2x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000755958	SCV001501791	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	COL3A1: BP4, BP7
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277193	SCV002565628	uncertain significance	Ehlers-Danlos syndrome	2020-03-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000313108	SCV004826028	benign	Ehlers-Danlos syndrome, type 4	2024-02-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530078	SCV004714826	likely benign	COL3A1-related disorder	2022-08-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).