Submissions for variant NM_000093.5(COL5A1):c.3868G>A (p.Ala1290Thr)

gnomAD frequency: 0.00001  dbSNP: rs863223451

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195614	SCV000249824	uncertain significance	not provided	2014-08-13	criteria provided, single submitter	clinical testing	The A1290T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A1290T variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1290T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Moreover, a missense mutations in a nearby residue (E1292K) has been reported in association with EDS, supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available clinical and molecular information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.This variant was found in COL5A1,TAAD
Ambry Genetics	RCV002311038	SCV000319896	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2015-07-12	criteria provided, single submitter	clinical testing	The p.A1290T variant (also known as c.3868G>A), located in coding exon 49 of the COL5A1 gene, results from a G to A substitution at nucleotide position 3868. The alanine at codon 1290 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6049 samples (12098 alleles) with coverage at this position. 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 variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229050	SCV000549002	benign	Ehlers-Danlos syndrome, classic type, 1	2023-03-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277478	SCV002565731	likely benign	Ehlers-Danlos syndrome	2022-04-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000195614	SCV005331011	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	COL5A1: BP4