Submissions for variant NM_000090.4(COL3A1):c.586T>C (p.Ser196Pro)

gnomAD frequency: 0.00001  dbSNP: rs751350498

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181070	SCV000233346	uncertain significance	not provided	2019-04-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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 that this variant does not alter protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat. Although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (Stenson et al., 2014)
Color Diagnostics, LLC DBA Color Health	RCV001185490	SCV001351714	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-03-03	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 196 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 2/249386 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277437	SCV002565653	uncertain significance	Ehlers-Danlos syndrome	2021-01-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003633485	SCV004547416	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-08-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 196 of the COL3A1 protein (p.Ser196Pro). This variant is present in population databases (rs751350498, 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: 199712). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003633485	SCV005399111	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Dominant-negative is due to missense variants affecting glycine residues in the Gly-X-Y repeat within the triple helical region (PMID: 29346445), while loss-of-function is due to null alleles. (I) 0108 - This gene is associated with both recessive and dominant disease. There is currently no genotype-phenotype correlation between autosomal dominant Ehlers-Danlos syndrome (EDS), vascular type (MIM#130050) and autosomal recessive polymicrogyria with or without vascular-type EDS (MIM#618343). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant interfamilial and intrafamilial variability have been reported for the same pathogenic variants (PMID: 20301667). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (2 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated collagen triple helix region and affects the X of a Gly-X-Y repeat (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS twice by clinical laboratories in ClinVar. (I) 0904 - Non-segregation of this variant with the phenotype under investigation has been clearly demonstrated. This variant has been found to be inherited from an unaffected parent. (SB) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
All of Us Research Program, National Institutes of Health	RCV003633485	SCV005427256	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 196 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 2/249386 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.