ClinVar Genomic variation as it relates to human health

Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Rarity in general population databases (dbsnp, esp, 1000 genomes)

This missense variant replaces isoleucine with methionine at codon 66 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 been reported in one individual affected with Ehlers-Danlos syndrome hypermobility type or benign joint hypermobility syndrome (PMID: 27011056). This variant has been identified in 7/250798 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.

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 66 of the COL3A1 protein (p.Ile66Met). This variant is present in population databases (rs372269408, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome (PMID: 27011056). ClinVar contains an entry for this variant (Variation ID: 263619). 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.

BP4, PP2

This missense variant replaces isoleucine with methionine at codon 66 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 been reported in one individual affected with Ehlers-Danlos syndrome hypermobility type or benign joint hypermobility syndrome (PMID: 27011056). This variant has been identified in 7/250798 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.

Variant summary: COL3A1 c.198A>G (p.Ile66Met) results in a conservative amino acid change located in the VWFC domain (IPR001007) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250798 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.198A>G has been reported in the literature in the heterozygous state in 2 individuals affected with Ehlers-Danlos syndrome and/or Aortopathy (example, Weerakkody_2016, Wooderchak-Donahue_2012). These report(s) do not provide unequivocal conclusions about association of the variant with COL3A1-related conditions. Co-occurrences with other pathogenic variant(s) have been reported (FBN1 c.1585C>T, p.R529X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27011056, 23148498). ClinVar contains an entry for this variant (Variation ID: 263619). Based on the evidence outlined above, the variant was classified as uncertain significance.

Identified in an individual with hypermobility and coronary artery dissection who also harbors the COL5A2 p.(K743T) variant (PMID: 27011056); Reported as an additional variant present in a positive control sample harboring a pathogenic FBN1 nonsense variant; clinical information for the individual was not provided (PMID: 23148498); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); This variant is associated with the following publications: (PMID: 23148498, 27011056)