Submissions for variant NM_000090.4(COL3A1):c.992A>T (p.Gln331Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002287297	SCV002577569	likely pathogenic	Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2022-03-28	criteria provided, single submitter	clinical testing	PM2, PP2, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV003097721	SCV002987127	uncertain significance	Ehlers-Danlos syndrome, type 4	2021-09-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with leucine at codon 331 of the COL3A1 protein (p.Gln331Leu). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. 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.
All of Us Research Program, National Institutes of Health	RCV003097721	SCV004826730	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with leucine at codon 331 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.