Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002547593 | SCV003453066 | uncertain significance | COG5-congenital disorder of glycosylation | 2022-07-01 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 152 of the COG5 protein (p.Ile152Leu). This variant is present in population databases (rs138976539, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with COG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049086). 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. 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001354727 | SCV001549411 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The COG5 p.I152L variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs138976539) and in control databases in 41 of 282770 chromosomes at a frequency of 0.0001450, and was observed at the highest frequency in the African population in 37 of 24964 chromosomes (freq: 0.001482) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I152 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |