Submissions for variant NM_000090.4(COL3A1):c.1900C>T (p.Pro634Ser)

dbSNP: rs762129273

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001184701	SCV001350737	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 634 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 2/251106 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	RCV001595071	SCV001829304	uncertain significance	not provided	2019-05-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV002560861	SCV003485561	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 634 of the COL3A1 protein (p.Pro634Ser). This variant is present in population databases (rs762129273, gnomAD 0.002%). 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: 923776). 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.
Ambry Genetics	RCV001184701	SCV003999775	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-02	criteria provided, single submitter	clinical testing	The p.P634S variant (also known as c.1900C>T), located in coding exon 27 of the COL3A1 gene, results from a C to T substitution at nucleotide position 1900. The proline at codon 634 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in 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 alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV002560861	SCV004833107	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 634 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 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 2/251106 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.