Submissions for variant NM_000090.4(COL3A1):c.4073G>A (p.Arg1358Gln)

gnomAD frequency: 0.00002  dbSNP: rs745656610

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000251179	SCV000318487	uncertain significance	Cardiovascular phenotype	2013-02-12	criteria provided, single submitter	clinical testing	​The p.R1358Q variant (also known as c.4073G>A) is located in exon 50 of the COL3A1 gene. This alteration results from a G to A substitution at nucleotide position 4073. The arginine at codon 1358 is replaced by glutamine, an amino acid with highly similar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is well conserved in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000691	SCV001157729	uncertain significance	not specified	2018-07-14	criteria provided, single submitter	clinical testing	The COL3A1 c.4073G>A; p.Arg1358Gln variant (rs745656610), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is reported as uncertain significance by one laboratory in ClinVar (Variation ID: 263557), and is found in the general population with an overall allele frequency of 0.0012% (3/245964 alleles) in the Genome Aggregation Database. The arginine at codon 1358 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: deleterious) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the c.4073G>A; p.Arg1358Gln variant is uncertain at this time.
Color Diagnostics, LLC DBA Color Health	RCV001181617	SCV001346799	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1358 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with ascending aortic aneurysm (Weerakkody 2017, dissertation, Imperial College London) and in another individual affected with craniosynostosis (PMID: 37086723). This variant has been identified in 3/251220 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	RCV001553378	SCV001774237	uncertain significance	not provided	2023-04-07	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859444	SCV002242251	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1358 of the COL3A1 protein (p.Arg1358Gln). This variant is present in population databases (rs745656610, 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: 263557). 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 with a negative predictive value of 95%. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001553378	SCV002542000	uncertain significance	not provided	2021-08-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001859444	SCV004825631	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1358 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with ascending aortic aneurysm (Weerakkody 2017, dissertation, Imperial College London) and in another individual affected with craniosynostosis (PMID: 37086723). This variant has been identified in 3/251220 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.