Submissions for variant NM_000090.4(COL3A1):c.784A>G (p.Met262Val)

dbSNP: rs1688161240

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190093	SCV001357508	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 262 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001226764	SCV001399088	uncertain significance	Ehlers-Danlos syndrome, type 4	2019-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with valine at codon 262 of the COL3A1 protein (p.Met262Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with COL3A1-related conditions.
Fulgent Genetics, Fulgent Genetics	RCV002497663	SCV002782938	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001226764	SCV004831323	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 262 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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.