ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1526G>A (p.Arg509His)

gnomAD frequency: 0.00006  dbSNP: rs568986390
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489573 SCV000577583 uncertain significance not provided 2021-07-22 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 426985; Landrum et al., 2016)
Labcorp Genetics (formerly Invitae), Labcorp RCV000818956 SCV000959595 uncertain significance Ehlers-Danlos syndrome, type 4 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 509 of the COL3A1 protein (p.Arg509His). This variant is present in population databases (rs568986390, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 426985). 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 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.
Color Diagnostics, LLC DBA Color Health RCV001191863 SCV001359779 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-08-17 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 509 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 6/164704 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000489573 SCV002049791 uncertain significance not provided 2021-02-25 criteria provided, single submitter clinical testing The COL3A1 c.1526G>A; p.Arg509His variant (rs568986390), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 426985). This variant is found in the general population with an overall allele frequency of 0.003% (6/164704 alleles) in the Genome Aggregation Database. The arginine at codon 509 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.693). However, given the lack of clinical and functional data, the significance of the p.Arg509His variant is uncertain at this time.
Ambry Genetics RCV001191863 SCV002709657 likely benign Familial thoracic aortic aneurysm and aortic dissection 2024-03-21 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health RCV000818956 SCV004824603 uncertain significance Ehlers-Danlos syndrome, type 4 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 509 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 6/164704 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000489573 SCV005408941 uncertain significance not provided 2024-09-26 criteria provided, single submitter clinical testing BS1
GenomeConnect, ClinGen RCV002508936 SCV002818379 not provided Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome no assertion provided phenotyping only Variant classified as Uncertain significance and reported on 08-05-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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