ClinVar Genomic variation as it relates to human health

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper, no segs, ExAC: 3/8646 East Asian chromosomes

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Identified in a patient with non-syndromic thoracic aortic aneurysm/dissection (TAAD) (Sakai et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22001912)

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 40 of the COL3A1 protein (p.Ala40Val). This variant is present in population databases (rs201380807, gnomAD 0.02%). This missense change has been observed in individual(s) with aortic aneurysm and/or dissection (PMID: 22001912). ClinVar contains an entry for this variant (Variation ID: 199690). 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. 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.

This missense variant replaces alanine with valine at codon 40 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 an individual affected with aortic aneurysm and/or dissection (PMID: 22001912). This variant has been identified in 4/250932 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 missense variant replaces alanine with valine at codon 40 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with aortic aneurysm and/or dissection (PMID: 22001912). This variant has been identified in 4/250932 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.119C>T (p.Ala40Val) results in a non-conservative amino acid change located in the VWFC domain (IPR001007) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250932 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.119C>T has been reported in the literature as heterozygous genotype in an individual affected with Aortopathy without clinical specification (Sakai_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22001912). ClinVar contains an entry for this variant (Variation ID: 199690). Based on the evidence outlined above, the variant was classified as uncertain significance.