Submissions for variant NM_000090.4(COL3A1):c.1972G>A (p.Glu658Lys)

gnomAD frequency: 0.00001  dbSNP: rs189846410

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548065	SCV000631637	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-08-25	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: 459772). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is present in population databases (rs189846410, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 658 of the COL3A1 protein (p.Glu658Lys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780195	SCV000917255	uncertain significance	not specified	2022-12-18	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.1972G>A (p.Glu658Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250616 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.1972G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002461293	SCV002757297	uncertain significance	not provided	2022-11-22	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; 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); This variant is associated with the following publications: (PMID: 30837697, 30627513)
Fulgent Genetics, Fulgent Genetics	RCV002476117	SCV002793554	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-11-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003528190	SCV004362980	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 658 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 been identified in 2/250616 chromosomes 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	RCV000548065	SCV004833118	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 658 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 been identified in 2/250616 chromosomes 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	RCV003528190	SCV005568899	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-10-11	criteria provided, single submitter	clinical testing	The p.E658K variant (also known as c.1972G>A), located in coding exon 28 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1972. The glutamic acid at codon 658 is replaced by lysine, an amino acid with similar properties. This amino acid position is 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.