Submissions for variant NM_000090.4(COL3A1):c.3808C>A (p.Pro1270Thr)

gnomAD frequency: 0.00001  dbSNP: rs756724842

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703727	SCV000832641	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-05-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1270 of the COL3A1 protein (p.Pro1270Thr). This variant is present in population databases (rs756724842, gnomAD 0.0009%). This missense change has been observed in individual(s) with vascular Ehlers-Danlos (PMID: 25758994). ClinVar contains an entry for this variant (Variation ID: 580251). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001524998	SCV001734984	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 1270 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 been reported in two related individuals affected with vascular Ehlers-Danlos syndrome (PMID: 25758994). This variant has been identified in 1/250230 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.
GeneDx	RCV001759406	SCV001987729	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Reported in one individual with skin fragility, easy bruising, joint hypermobility, severe menometrorrhagia, characteristic facial appearance, and no vascular complications in the published literature (Frank et al., 2015); 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); This variant is associated with the following publications: (PMID: 25758994, 34318601)
All of Us Research Program, National Institutes of Health	RCV000703727	SCV004827636	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 1270 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 been reported in two related individuals affected with vascular Ehlers-Danlos syndrome (PMID: 25758994). This variant has been identified in 1/250230 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.
Ambry Genetics	RCV001524998	SCV005103891	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-04-22	criteria provided, single submitter	clinical testing	The p.P1270T variant (also known as c.3808C>A), located in coding exon 48 of the COL3A1 gene, results from a C to A substitution at nucleotide position 3808. The proline at codon 1270 is replaced by threonine, an amino acid with highly similar properties. This alteration was reported in a vascular Ehlers-Danlos syndrome (EDS) cohort (Frank M et al. Eur J Hum Genet, 2015 Dec;23:1657-64). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.