Submissions for variant NM_006348.5(COG5):c.1776T>C (p.Ala592=)

gnomAD frequency: 0.00142  dbSNP: rs142970891

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000364992	SCV000466033	uncertain significance	COG5-congenital disorder of glycosylation	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000431642	SCV000521823	likely benign	not specified	2017-11-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000364992	SCV002369084	benign	COG5-congenital disorder of glycosylation	2024-01-27	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000364992	SCV001445935	likely benign	COG5-congenital disorder of glycosylation	2020-11-16	no assertion criteria provided	curation	The heterozygous c.1869T>C variant in COG5 was identified by our study in the compound heterozygous state, along with a variant of unknown significance, in 1 individual with congenital disorder of glycosylation, type IIi (commonly referred to as COG5-CDG or CDG2I). The variant has not been previously reported in individuals with COG5-CDG and has been identified in 0.29% (30/10352) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs142970891). This variant has also been reported in ClinVar (Variation ID#: 358457) as likely benign by GeneDx and as uncertain significance by Illumina Clinical Services Laboratory. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BP7 (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV004725184	SCV005339382	likely benign	COG5-related disorder	2024-08-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).