Submissions for variant NM_000090.4(COL3A1):c.2665A>T (p.Asn889Tyr)

gnomAD frequency: 0.00001  dbSNP: rs761469859

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181099	SCV000233375	uncertain significance	not provided	2013-02-25	criteria provided, single submitter	clinical testing	p.Asn889Tyr (AAC>TAC): c.2665 A>T in exon 39 of the COL3A1 gene (NM_000090.3) The Asn889Tyr variant in the COL3A1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asn889Tyr results in a semi-conservative amino acid substitution of neutral, polar Asparagine with a larger neutral, polar Tyrosine at a position that is conserved in mammals. Mutations in nearby codons (Gly882Asn, Gly894Asp) have been reported in association with Ehlers-Danlos syndrome (EDS), supporting the functional importance of this region of the protein. The Asn889Tyr variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, in silico analysis predictions are conflicting regarding the effect of Asn889Tyr on the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if Asn889Tyr is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s).
Color Diagnostics, LLC DBA Color Health	RCV000778020	SCV000914130	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with tyrosine at codon 889 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 3/276064 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810829	SCV000951065	uncertain significance	Ehlers-Danlos syndrome, type 4	2018-12-10	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 199733). This variant is present in population databases (rs761469859, ExAC 0.002%). This sequence change replaces asparagine with tyrosine at codon 889 of the COL3A1 protein (p.Asn889Tyr). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and tyrosine.
Fulgent Genetics, Fulgent Genetics	RCV002485187	SCV002792606	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-09-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000810829	SCV004833791	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with tyrosine at codon 889 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 3/276064 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.