Submissions for variant NM_000090.4(COL3A1):c.4357G>A (p.Asp1453Asn)

gnomAD frequency: 0.00001  dbSNP: rs1131691353

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494257	SCV000581938	uncertain significance	not provided	2024-09-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD)
Color Diagnostics, LLC DBA Color Health	RCV001188961	SCV001356152	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1453 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 not been identified 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	RCV002475974	SCV002794029	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-11-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000509367	SCV003295208	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-10-21	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 1453 of the COL3A1 protein (p.Asp1453Asn). This variant is not present in population databases (gnomAD no frequency). 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: 429381). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV001188961	SCV005568898	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-11-15	criteria provided, single submitter	clinical testing	The p.D1453N variant (also known as c.4357G>A), located in coding exon 51 of the COL3A1 gene, results from a G to A substitution at nucleotide position 4357. The aspartic acid at codon 1453 is replaced by asparagine, an amino acid with highly similar properties. This variant has been observed in at least one individual with a personal and/or family history of aortic aneurysm/dilation (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GenomeConnect, ClinGen	RCV000509367	SCV000607217	not provided	Ehlers-Danlos syndrome, type 4		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.