Submissions for variant NM_000090.4(COL3A1):c.1351G>A (p.Glu451Lys)

dbSNP: rs1559056438

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000680211	SCV001204736	pathogenic	Ehlers-Danlos syndrome, type 4	2023-05-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 451 of the COL3A1 protein (p.Glu451Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of vascular Ehlers-Danlos syndrome (PMID: 30837697; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 561178). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL3A1 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001771925	SCV001994642	uncertain significance	not provided	2019-03-18	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Occurs in the triple helical domain at the X 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 X position is not a common mechanism of disease (Stenson et al., 2014); Other COL3A1 variants that result in a X-position substitution of glutamic acid with lysine have been reported in association with EDS; however, it is unknown whether this variant would have similar effect (Ghali et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30837697)
Ambry Genetics	RCV004822158	SCV005568904	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-09-16	criteria provided, single submitter	clinical testing	The p.E451K variant (also known as c.1351G>A), located in coding exon 20 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1351. The glutamic acid at codon 451 is replaced by lysine, an amino acid with similar properties. This variant was identified in one or more individuals with features consistent with vascular Ehlers-Danlos syndrome (EDS) and segregated with disease in at least one family (Ghali N et al. Genet Med, 2019 Sep;21:2081-2091; Colman M et al. Clin Exp Rheumatol, 2022 May;40 Suppl 134:46-62; external communication; Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Division of Medical Genetics at University of Versailles, Paris Saclay University	RCV000680211	SCV000804463	likely pathogenic	Ehlers-Danlos syndrome, type 4		no assertion criteria provided	clinical testing	Spontaneous perforation of sigmoid colon started at age 41.