ClinVar Miner

Submissions for variant NM_000089.4(COL1A2):c.1246G>A (p.Val416Ile)

gnomAD frequency: 0.00003  dbSNP: rs550867796
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002231006 SCV000627291 likely benign Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 2023-12-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757107 SCV000885221 uncertain significance not provided 2018-02-09 criteria provided, single submitter clinical testing The COL1A2 c.1246G>A; p.Val416Ile variant (rs550867796), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 0.06% (identified on 17 out of 30,782 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 456803).The valine at position 416 is highly conserved, considering 11 species, and computational analyses of the effects of the p.Val416Ile variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Val416Ile variant cannot be determined with certainty.
GeneDx RCV000757107 SCV001823076 uncertain significance not provided 2019-09-03 criteria provided, single submitter clinical testing Has not been reported in association with connective tissue disorders to the best of our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 456803; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28991257)
Neuberg Centre For Genomic Medicine, NCGM RCV003338649 SCV004048425 uncertain significance Osteogenesis imperfecta type III criteria provided, single submitter clinical testing The missense variant p.Val416Ile in COL1A2 (NM_000089.4) has been reported to the ClinVar database with conflicting interpretation of pathogenicity [Uncertain significance/ likely benign]. The p.Val416Ile variant has allele frequency of 0.008% in the gnomAD Exomes database. The amino acid Val at position 416 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Val416Ile in COL1A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS).

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