Submissions for variant NM_198576.4(AGRN):c.2650C>T (p.Arg884Cys)

dbSNP: rs539990009

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000425529	SCV000533733	uncertain significance	not provided	2016-11-18	criteria provided, single submitter	clinical testing	The R884C variant in the AGRN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R884C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R884C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R884C as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851071	SCV002136646	uncertain significance	Congenital myasthenic syndrome 8	2022-11-08	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 390809). This variant has not been reported in the literature in individuals affected with AGRN-related conditions. This variant is present in population databases (rs539990009, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 884 of the AGRN protein (p.Arg884Cys).
Ambry Genetics	RCV005328267	SCV005996905	uncertain significance	Inborn genetic diseases	2025-01-30	criteria provided, single submitter	clinical testing	The c.2650C>T (p.R884C) alteration is located in exon 15 (coding exon 15) of the AGRN gene. This alteration results from a C to T substitution at nucleotide position 2650, causing the arginine (R) at amino acid position 884 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.