ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.4450G>A (p.Gly1484Ser) (rs147420365)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619624 SCV000738691 likely benign Cardiovascular phenotype 2017-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification,Other strong data supporting benign classification
GeneDx RCV000195469 SCV000249947 uncertain significance not provided 2018-11-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A2 gene. The G1484S variant has not been published as pathogenic or been reported as benign to our knowledge, yet this variant has been identified independently and/or in conjunction with additional variants in other unrelated individuals referred for genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals. The G1484S variant is observed in 80/126,512 (0.06%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Finally, though G1484S is a non-conservative amino acid substitution, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000464769 SCV000547865 uncertain significance Ehlers-Danlos syndrome, classic type 2018-06-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1484 of the COL5A2 protein (p.Gly1484Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs147420365, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213086). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.

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