Submissions for variant NM_000090.4(COL3A1):c.3413C>T (p.Pro1138Leu)

gnomAD frequency: 0.00014  dbSNP: rs201880122

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473742	SCV000541812	likely benign	Ehlers-Danlos syndrome, type 4	2023-12-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000772083	SCV000905115	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1138 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 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 55/282810 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.
Illumina Laboratory Services, Illumina	RCV000473742	SCV001296730	benign	Ehlers-Danlos syndrome, type 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV001775799	SCV002013249	uncertain significance	not provided	2022-12-06	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 has a deleterious effect on 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 (HGMD)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000772083	SCV004240467	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000473742	SCV004829649	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1138 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 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 55/282810 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.
Ambry Genetics	RCV000772083	SCV005032220	benign	Familial thoracic aortic aneurysm and aortic dissection	2024-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001775799	SCV005408948	uncertain significance	not provided	2024-08-26	criteria provided, single submitter	clinical testing	BS1
PreventionGenetics, part of Exact Sciences	RCV004735529	SCV005346760	uncertain significance	COL3A1-related disorder	2024-06-18	no assertion criteria provided	clinical testing	The COL3A1 c.3413C>T variant is predicted to result in the amino acid substitution p.Pro1138Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.