Submissions for variant NM_000090.4(COL3A1):c.4088G>A (p.Arg1363Gln)

dbSNP: rs1227282800

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001191499	SCV001359332	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1363 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 been identified in 1/251148 chromosomes 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.
GeneDx	RCV001799742	SCV002044151	uncertain significance	not provided	2021-12-16	criteria provided, single submitter	clinical testing	Has not been previously published in association with COL3A1-related disorders to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 927926; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 34382383)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001863038	SCV002167588	uncertain significance	Ehlers-Danlos syndrome, type 4	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 1363 of the COL3A1 protein (p.Arg1363Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). 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: 927926). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function. 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.
All of Us Research Program, National Institutes of Health	RCV001863038	SCV004828130	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1363 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 been identified in 1/251148 chromosomes 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.