Submissions for variant NM_000090.4(COL3A1):c.3869T>C (p.Ile1290Thr)

dbSNP: rs1688690716

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001185925	SCV001352236	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1290 of the COL3A1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in three related individuals affected with thoracic aortic aneurysm and dissection and in one unaffected adult family member (PMID: 27146836). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001876177	SCV002288338	uncertain significance	Ehlers-Danlos syndrome, type 4	2021-01-13	criteria provided, single submitter	clinical testing	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. 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 expected to disrupt COL3A1 protein function. This variant has been observed in individual(s) with thoracic aortic aneurysm and/or dissection (PMID: 27146836). ClinVar contains an entry for this variant (Variation ID: 924552). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 1290 of the COL3A1 protein (p.Ile1290Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine.
GeneDx	RCV003227926	SCV003924653	uncertain significance	not provided	2022-11-11	criteria provided, single submitter	clinical testing	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: 27146836)
All of Us Research Program, National Institutes of Health	RCV001876177	SCV004827714	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 1290 of the COL3A1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in three related individuals affected with thoracic aortic aneurysm and dissection and in one unaffected adult family member (PMID: 27146836). 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.