Submissions for variant NM_000090.4(COL3A1):c.515A>C (p.Tyr172Ser)

gnomAD frequency: 0.00001  dbSNP: rs771654029

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001186234	SCV000319502	benign	Familial thoracic aortic aneurysm and aortic dissection	2023-08-25	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	RCV000389469	SCV000425501	benign	Ehlers-Danlos syndrome, type 4	2018-01-13	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	RCV000389469	SCV000831640	likely benign	Ehlers-Danlos syndrome, type 4	2025-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001186234	SCV001352602	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-11-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001564374	SCV001787531	likely benign	not provided	2020-09-17	criteria provided, single submitter	clinical testing	Occurs in the triple helical domain at the {X} position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (Stenson et al., 2014)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278235	SCV002565650	uncertain significance	Ehlers-Danlos syndrome	2020-11-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001564374	SCV003916217	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	COL3A1: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238797	SCV005884262	likely benign	not specified	2024-12-10	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.515A>C (p.Tyr172Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250950 control chromosomes. The observed variant frequency is approximately 64-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Ehlers-Danlos Syndrome, Vascular Type phenotype (1.5e-06), providing evidence for a benign role of the variant. c.515A>C has been reported in the literature in at least one individual affected with Ehlers-Danlos Syndrome, Vascular Type (e.g. Leone_2023). In this patient, a co-occurrence with an additional variant (c.3572G>A, p.(Gly1191Asp)) was reported, providing additional evidence for a benign role of the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37079061). ClinVar contains an entry for this variant (Variation ID: 263946). Based on the evidence outlined above, the variant was classified as likely benign.