Submissions for variant NM_000090.4(COL3A1):c.3764G>A (p.Arg1255His)

gnomAD frequency: 0.00002  dbSNP: rs368119434

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000774351	SCV000908053	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1255 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 been identified in 5/251096 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001305235	SCV001494560	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1255 of the COL3A1 protein (p.Arg1255His). This variant is present in population databases (rs368119434, gnomAD 0.01%). This missense change has been observed in individual(s) with sporadic thoracic aortic dissection (PMID: 34047934). ClinVar contains an entry for this variant (Variation ID: 629641). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV002462127	SCV002757222	uncertain significance	not provided	2022-08-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); This variant is associated with the following publications: (PMID: 34047934)
All of Us Research Program, National Institutes of Health	RCV001305235	SCV004827547	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1255 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 5/251096 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.