Submissions for variant NM_000090.4(COL3A1):c.1662C>T (p.Pro554=)

gnomAD frequency: 0.00003  dbSNP: rs373963384

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548509	SCV000631631	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-07-30	criteria provided, single submitter	clinical testing	This sequence change affects codon 554 of the COL3A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL3A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs373963384, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 459767). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000772103	SCV000905139	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-10	criteria provided, single submitter	clinical testing	This synonymous variant does not change the amino acid sequence of the COL3A1 protein. However, computational splicing tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001770419	SCV001994447	uncertain significance	not provided	2019-08-20	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Ambry Genetics	RCV000772103	SCV002703308	benign	Familial thoracic aortic aneurysm and aortic dissection	2021-11-29	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.
All of Us Research Program, National Institutes of Health	RCV000548509	SCV004824725	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-13	criteria provided, single submitter	clinical testing	This synonymous variant does not change the amino acid sequence of the COL3A1 protein. However, computational splicing tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.