Submissions for variant NM_000642.3(AGL):c.2248G>T (p.Ala750Ser)

gnomAD frequency: 0.00014  dbSNP: rs139950099

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000311437	SCV000346076	uncertain significance	Glycogen storage disease type III	2018-01-12	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	RCV000423215	SCV000524779	uncertain significance	not provided	2020-10-27	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Invitae	RCV000311437	SCV000752137	uncertain significance	Glycogen storage disease type III	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 750 of the AGL protein (p.Ala750Ser). This variant is present in population databases (rs139950099, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with AGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 291337). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AGL protein function. 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.
Genome-Nilou Lab	RCV000311437	SCV002055108	uncertain significance	Glycogen storage disease type III	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000311437	SCV002800775	uncertain significance	Glycogen storage disease type III	2021-10-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518171	SCV003750348	uncertain significance	Inborn genetic diseases	2021-04-21	criteria provided, single submitter	clinical testing	The c.2248G>T (p.A750S) alteration is located in exon 17 (coding exon 16) of the AGL gene. This alteration results from a G to T substitution at nucleotide position 2248, causing the alanine (A) at amino acid position 750 to be replaced by a serine (S). The p.A750S alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000311437	SCV001457979	uncertain significance	Glycogen storage disease type III	2020-01-17	no assertion criteria provided	clinical testing