Submissions for variant NM_000090.4(COL3A1):c.1694C>A (p.Pro565His)

gnomAD frequency: 0.00011  dbSNP: rs144260440

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468911	SCV000541814	uncertain significance	Ehlers-Danlos syndrome, type 4	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline with histidine at codon 565 of the COL3A1 protein (p.Pro565His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs144260440, ExAC 0.04%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV001189975	SCV001357376	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces proline with histidine at codon 565 of the COL3A1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 9/282690 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	RCV001192745	SCV001361055	uncertain significance	not specified	2019-07-29	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.1694C>A (p.Pro565His) results in a non-conservative amino acid change located in the Collagen triple helix repeat domain (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251376 control chromosomes (gnomAD). 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.1694C>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001584127	SCV001812373	uncertain significance	not provided	2021-09-20	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 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).; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 404308; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918)
Fulgent Genetics, Fulgent Genetics	RCV002502602	SCV002814062	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-09-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000468911	SCV004824770	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-08-15	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the triple-helical region of the COL3A1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/277102 chromosomes (9/24024 African chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.