Submissions for variant NM_000090.4(COL3A1):c.4276A>G (p.Lys1426Glu)

gnomAD frequency: 0.00001  dbSNP: rs908421014

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587798	SCV000695375	uncertain significance	not provided	2017-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001180322	SCV001345221	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1426 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 been reported in an individual affected with adolescent idiopathic scoliosis, who had a Ghent systemic score of 3 (PMID:26333736). 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.
All of Us Research Program, National Institutes of Health	RCV004002398	SCV004828253	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1426 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004002398	SCV005767990	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1426 of the COL3A1 protein (p.Lys1426Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adolescent idiopathic scoliosis (PMID: 26333736). ClinVar contains an entry for this variant (Variation ID: 495546). 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.