Submissions for variant NM_000090.4(COL3A1):c.1165A>T (p.Asn389Tyr)

gnomAD frequency: 0.00006  dbSNP: rs200394946

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181079	SCV000233355	uncertain significance	not provided	2024-07-09	criteria provided, single submitter	clinical testing	Reported in a female with internal carotid dissection and skin hyperelasticity, whose mother with carotid artery dissection also harbored the same variant (PMID: 25758994); Reported in an individual with younger-onset small vessel disease (PMID: 31719132); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y 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 Y position is not a common mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 34318601, 33974636, 25758994, 31719132)
Ambry Genetics	RCV000778019	SCV000320669	benign	Familial thoracic aortic aneurysm and aortic dissection	2022-09-07	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465133	SCV000541785	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 389 of the COL3A1 protein (p.Asn389Tyr). This variant is present in population databases (rs200394946, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome or stroke (PMID: 25758994, 31719132). ClinVar contains an entry for this variant (Variation ID: 199718). 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	RCV002478603	SCV000896914	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-08-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000778019	SCV000914129	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with tyrosine at codon 389 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 performed for this variant. This variant has been reported in an individual affected with possible vascular Ehlers-Danlos syndrome (PMID: 25758994). This variant has been identified in 28/282770 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.
Revvity Omics, Revvity	RCV000181079	SCV003828137	uncertain significance	not provided	2021-06-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000465133	SCV004826885	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with tyrosine at codon 389 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 performed for this variant. This variant has been reported in an individual affected with possible vascular Ehlers-Danlos syndrome (PMID: 25758994). This variant has been identified in 28/282770 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	RCV004537521	SCV004108469	uncertain significance	COL3A1-related disorder	2024-01-22	no assertion criteria provided	clinical testing	The COL3A1 c.1165A>T variant is predicted to result in the amino acid substitution p.Asn389Tyr. This variant has been reported in an individual with possible classical Ehlers-Danlos syndrome (Supplementary results 2, Group 3 and Supplementary Table 4c, Frank et al 2015. PubMed ID: 25758994). This variant was also reported in a study analyzing the frequency of variants identified in small vessel disease (SVD) associated genes in individuals with younger-onset apparently sporadic SVD stroke (Tan et al. 2019. PubMed ID: 31719132) and in a study of individuals with Chiari malformation type 1 (Reported as rs200394946, Table S5, Urbizu et al. 2021. PubMed ID: 33974636). This variant is reported in 0.021% 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.