Submissions for variant NM_000090.4(COL3A1):c.266C>T (p.Pro89Leu)

gnomAD frequency: 0.00006  dbSNP: rs139610730

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001170884	SCV000319269	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-05-29	criteria provided, single submitter	clinical testing	The c.266C>T (p.P89L) alteration is located in exon 2 (coding exon 2) of the COL3A1 gene. This alteration results from a C to T substitution at nucleotide position 266, causing the proline (P) at amino acid position 89 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001707606	SCV000583216	uncertain significance	not provided	2024-08-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553256	SCV000631646	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the COL3A1 protein (p.Pro89Leu). This variant is present in population databases (rs139610730, gnomAD 0.01%). This missense change has been observed in individual(s) with Ehlers-Danlos syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 263835). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170884	SCV001333506	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-06-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170884	SCV001359780	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 89 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 13/281694 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.
Fulgent Genetics, Fulgent Genetics	RCV002503958	SCV002814947	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-08-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000553256	SCV004830683	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 89 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 13/281694 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.