ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.1156C>T (p.Pro386Ser) (rs757192342)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250222 SCV000319234 uncertain significance Cardiovascular phenotype 2019-02-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000481073 SCV000568121 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing The P386S variant in the COL3A1 gene has been reported previously in an individual with an additional COL3A1 variant; however, phase was not known and no other phenotypic or segregation information was provided (Pepin et al., 2016). The P386S variant is observed in 1/24,018 (0.004%) alleles from individuals of African background and 6/277,110 (0.002%) total alleles in large population cohorts (Lek et al., 2016). The P386S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P386S as a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780197 SCV000917257 uncertain significance not specified 2018-04-30 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.1156C>T (p.Pro386Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat domain 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 2.2e-05 in 277110 control chromosomes. Although this frequency exceeds the maximal expected allele frequency for a pathogenic variant in COL3A1, this data must be interpreted cautiously since only 6 alleles were present in gnomAD and cardiac phenotypes may be present in the gnomAD dataset. c.1156C>T has been reported in the literature by a reputed diagnostic laboratory (Collagen Diagnostic Laboratory, Pepin et al, 2016) in one individual and was classified as "Likely Benign". A separate mutation with phase unknown was reportedly identified in this proband, however, this report does not provide unequivocal conclusions about an association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV001057358 SCV001221845 uncertain significance Ehlers-Danlos syndrome, type 4 2019-08-14 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 386 of the COL3A1 protein (p.Pro386Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs757192342, ExAC 0.003%). This variant has not been reported in the literature in individuals with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 263816). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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 RCV001191119 SCV001358816 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-12-31 criteria provided, single submitter clinical testing

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