Submissions for variant NM_000090.4(COL3A1):c.3163G>A (p.Val1055Ile)

gnomAD frequency: 0.00001  dbSNP: rs747197616

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589571	SCV000695370	uncertain significance	not provided	2016-02-22	criteria provided, single submitter	clinical testing	Variant summary: This c.3163G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Val to Ile. 3/4 in-silico tools used predict this variant to be benign. This variant was found in 2/121108 control chromosomes at a frequency of 0.0000165, which is more than 12 times greater than the maximal expected frequency of a pathogenic allele (0.0000013) in this gene, suggesting this variant is a benign rare polymorphism. This variant has been found in at least one Glioma sample as a somatic occurrence without strong evidence for causality (Suzuki_20105). The variant of interest has not been reported in affected individuals via reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, this variant has currently been classified as a VUS-possibly benign until more information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001189481	SCV001356787	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1055 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). 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251354 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860117	SCV002198762	uncertain significance	Ehlers-Danlos syndrome, type 4	2021-08-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 1055 of the COL3A1 protein (p.Val1055Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs747197616, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 495544). 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.