Submissions for variant NM_015386.3(COG4):c.1546G>A (p.Gly516Arg)

dbSNP: rs1555575860

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522988	SCV000618093	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant increase in core proteins of HSPGs accumulation on the cell surface of G516R mutant cell lines and increased secretion of the SIL1 protein; findings which support a gain of function effect of the G516R variant (Sumya et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34603392, 31949312, 30290151, 33688625, 34595172, 35455576, 36393834)
Undiagnosed Diseases Network, NIH	RCV000625979	SCV000746583	pathogenic	COG4-congenital disorder of glycosylation	2017-08-23	criteria provided, single submitter	research	This individual has been reported in PMID: 30290151.
SIB Swiss Institute of Bioinformatics	RCV000710020	SCV000996399	pathogenic	Microcephalic osteodysplastic dysplasia, Saul-Wilson type	2019-07-11	criteria provided, single submitter	curation	This variant is interpreted as a Pathogenic for Saul-Wilson syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2; PS4-Moderate; PM6-Strong; PP3; PS3
Ambry Genetics	RCV001266583	SCV001444759	pathogenic	Inborn genetic diseases	2021-09-17	criteria provided, single submitter	clinical testing	The c.1546G>A (p.G516R) alteration is located in exon 12 (coding exon 12) of the COG4 gene. This alteration results from a G to A substitution at nucleotide position 1546, causing the glycine (G) at amino acid position 516 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The p.G516R alteration has been reported as a recurrent de novo alteration in several patients with Saul-Wilson syndrome (Ferreira, 2018). This amino acid position is highly conserved in available vertebrate species. Fibroblasts from patients with the p.G516R alteration have been shown to have abnormal Golgi morphology and decreased Golgi volume compared to control samples. Glycan analysis and glycosylation status were not measurably different between patients and controls; however there was evidence of altered Golgi-dependent glycosylation and abnormal Golgi trafficking in patients (Ferreira, 2018) . The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV000522988	SCV002017407	pathogenic	not provided	2020-03-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000522988	SCV002817259	pathogenic	not provided	2020-10-08	criteria provided, single submitter	clinical testing	This variant appears to occur de novo in an individual tested at Athena Diagnostics and in multiple individuals with clinical features consistent with autosomal dominant Saul-Wilson syndrome (PMID 30290151). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
OMIM	RCV000710020	SCV000840385	pathogenic	Microcephalic osteodysplastic dysplasia, Saul-Wilson type	2018-11-29	no assertion criteria provided	literature only
GeneReviews	RCV000710020	SCV001245260	not provided	Microcephalic osteodysplastic dysplasia, Saul-Wilson type		no assertion provided	literature only