Submissions for variant NM_000090.4(COL3A1):c.2773G>A (p.Asp925Asn)

gnomAD frequency: 0.00001  dbSNP: rs929526823

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002314211	SCV000738507	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-07-15	criteria provided, single submitter	clinical testing	The p.D925N variant (also known as c.2773G>A), located in coding exon 39 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2773. The aspartic acid at codon 925 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved through mammals but not in all 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 alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001212769	SCV001384366	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 925 of the COL3A1 protein (p.Asp925Asn). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 519595). 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.
Fulgent Genetics, Fulgent Genetics	RCV002483726	SCV002781408	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-11-04	criteria provided, single submitter	clinical testing
GeneDx	RCV003153762	SCV003842390	uncertain significance	not provided	2022-09-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense 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 (HGMD); Has not been previously published as pathogenic or benign to our knowledge
All of Us Research Program, National Institutes of Health	RCV001212769	SCV004833879	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 925 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 1/31392 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.
PreventionGenetics, part of Exact Sciences	RCV004735680	SCV005346495	uncertain significance	COL3A1-related disorder	2024-03-08	no assertion criteria provided	clinical testing	The COL3A1 c.2773G>A variant is predicted to result in the amino acid substitution p.Asp925Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% 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.