ClinVar Genomic variation as it relates to human health

Variant summary: COL3A1 c.1156C>T (p.Pro386Ser) results in a non-conservative amino acid change located in the third collagen triple helix repeat domain (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 1.6e-05 in 251340 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1156C>T has been reported in the literature in at least one individual (Pepin_2015). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. Co-occurrence with a pathogenic variant has been reported (SMAD3 c.532+1G>C), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This missense variant replaces proline with serine at codon 386 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 6/282734 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 proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 386 of the COL3A1 protein (p.Pro386Ser). This variant is present in population databases (rs757192342, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 263816). 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.

This missense variant replaces proline with serine at codon 386 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 6/282734 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.

The c.1156C>T (p.P386S) alteration is located in exon 17 (coding exon 17) of the COL3A1 gene. This alteration results from a C to T substitution at nucleotide position 1156, causing the proline (P) at amino acid position 386 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Has been reported in an individual who harbored an additional COL3A1 variant; however, phase was not known and no clinical or segregation details were provided (PMID: 25834947); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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 (HGMD); This variant is associated with the following publications: (PMID: 25834947)