Submissions for variant NM_000090.4(COL3A1):c.3299G>A (p.Arg1100His)

gnomAD frequency: 0.00013  dbSNP: rs370069953

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001183250	SCV001348931	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1100 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 12/282104 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194122	SCV001363411	likely benign	not specified	2019-09-03	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.3299G>A (p.Arg1100His) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 282104 control chromosomes (gnomAD). The observed variant frequency is approximately 34 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3299G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV001210034	SCV001381498	benign	Ehlers-Danlos syndrome, type 4	2023-10-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001732066	SCV001982334	uncertain significance	not provided	2021-03-25	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 does not alter 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 (ClinVar Variant ID# 922907; Landrum et al., 2016)
Ambry Genetics	RCV001183250	SCV002611985	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-03-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001183250	SCV004240466	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-07	criteria provided, single submitter	clinical testing