Submissions for variant NM_020751.3(COG6):c.1759C>T (p.Arg587Cys)

gnomAD frequency: 0.00061  dbSNP: rs144843064

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000386062	SCV000384381	uncertain significance	COG6-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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850650	SCV002123012	uncertain significance	COG6-congenital disorder of glycosylation; Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 587 of the COG6 protein (p.Arg587Cys). This variant is present in population databases (rs144843064, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with COG6-related conditions. ClinVar contains an entry for this variant (Variation ID: 312148). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COG6 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002520885	SCV003574121	uncertain significance	Inborn genetic diseases	2022-04-13	criteria provided, single submitter	clinical testing	The c.1759C>T (p.R587C) alteration is located in exon 18 (coding exon 18) of the COG6 gene. This alteration results from a C to T substitution at nucleotide position 1759, causing the arginine (R) at amino acid position 587 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.