Submissions for variant NM_000090.4(COL3A1):c.1885A>G (p.Lys629Glu)

gnomAD frequency: 0.00002  dbSNP: rs1466862530

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795126	SCV000934569	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-09-23	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 not expected to disrupt COL3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 641803). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 629 of the COL3A1 protein (p.Lys629Glu).
GeneDx	RCV001557694	SCV001779501	uncertain significance	not provided	2019-02-22	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 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 (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV002493453	SCV002775369	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117583	SCV003800623	uncertain significance	not specified	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.1885A>G (p.Lys629Glu) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251152 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1885A>G in individuals affected with Ehlers-Danlos Syndrome, Vascular Type and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV003528234	SCV004362978	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 629 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 COL3A1-related 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.
All of Us Research Program, National Institutes of Health	RCV000795126	SCV004827370	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 629 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 COL3A1-related 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.
Ambry Genetics	RCV003528234	SCV005568929	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-10-25	criteria provided, single submitter	clinical testing	The p.K629E variant (also known as c.1885A>G), located in coding exon 27 of the COL3A1 gene, results from an A to G substitution at nucleotide position 1885. The lysine at codon 629 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.