Submissions for variant NM_000090.4(COL3A1):c.4301G>A (p.Arg1434His)

gnomAD frequency: 0.00010  dbSNP: rs138533702

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000693580	SCV000821453	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-01-09	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 1434 of the COL3A1 protein (p.Arg1434His). This variant is present in population databases (rs138533702, gnomAD 0.03%). 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: 572244). 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.
Color Diagnostics, LLC DBA Color Health	RCV001179593	SCV001344295	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1434 of the COL3A1 protein. Computational prediction tool indicates that this variant may have a neutral impact on protein structure and function. 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 12/282722 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.
Institute of Human Genetics, University Hospital Muenster	RCV000693580	SCV002499689	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-03-31	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP3
Ambry Genetics	RCV001179593	SCV003745659	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2022-05-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV003235354	SCV003932966	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
All of Us Research Program, National Institutes of Health	RCV000693580	SCV004828298	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1434 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 cardiovascular disorders in the literature. This variant has been identified in 12/282722 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.