Submissions for variant NM_000642.3(AGL):c.334A>G (p.Ile112Val)

gnomAD frequency: 0.00064  dbSNP: rs147024351

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000299112	SCV000346056	uncertain significance	Glycogen storage disease type III	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	RCV000299112	SCV000626726	likely benign	Glycogen storage disease type III	2024-01-31	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000299112	SCV000845641	likely benign	Glycogen storage disease type III	2018-08-07	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000299112	SCV002055520	likely benign	Glycogen storage disease type III	2021-07-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000786275	SCV002540877	uncertain significance	not provided	2021-12-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002518170	SCV003538799	uncertain significance	Inborn genetic diseases	2022-05-09	criteria provided, single submitter	clinical testing	The c.334A>G (p.I112V) alteration is located in exon 4 (coding exon 3) of the AGL gene. This alteration results from a A to G substitution at nucleotide position 334, causing the isoleucine (I) at amino acid position 112 to be replaced by a valine (V). The p.I112V alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000786275	SCV004032964	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	AGL: BP4
Baylor Genetics	RCV000299112	SCV004041033	uncertain significance	Glycogen storage disease type III	2023-02-16	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786275	SCV000925030	uncertain significance	not provided	2017-11-07	no assertion criteria provided	provider interpretation	p.Ile112Val (c.334A>G) in exon 4 of the AGL gene (NM_000642.2; chr1-100327853-A-G) - SCICD classification: variant of uncertain significance, likely benign SCICD Classification: variant of uncertain significance, likely benign based on mode of inheritance (must be autosomal recessive to cause disease), relatively high frequency in the general population and lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Lab Classification (Invitae): variant of uncertain significance Gene-level evidence: AGL: The AGL gene encodes the glycogen debrancher enzyme. Deficiency of this enzyme causes glycogen storage disease IIIb (GSDIII aka Cori disease). This is an autosomal recessive disorder with a spectrum of manifestations that include hypoglycemia, hyperlipidemia, hepatic dysfunction. Some individuals have neuromuscular disease and cardiomyopathy. A person with a single disease causing variant is a carrier and two disease-causing variants lead to clinical manifestations. Case data (not including our patient): Our patient does not have inherited cardiovascular disease per evaluation. Patient was referred to our lab due to another pathogenic MYBPC3 variant identified via 23andMe and Promethease data. We sent a panel. The variant in MYBPC3 did not clinically confirm. ClinVar: Illumina Clinical labs - no details provided Cases in the literature: This variant is mentioned in a textbook by Wyandt, called Human Chromosome Variation. This individual had glycogen storage disease III and the authors classified this variant as a VUS. Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"." Conservation data: The isoleucine at codon 112 is not conserved across species. A valine is present in many other species. Neighboring amino acids are completely conserved. Nearby pathogenic variants at this codon or neighboring codons: A synonymous variant is present at a nearby residue, p.Tyr106Tyr and is classified as a VUS by Illumina Clinical labs. No Population data: Highest MAF in European population: 0.1%. The variant was reported online in 187 of 136,607 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 153 of 63,354 individuals of European descent (MAF=0.1%), 23 of 15,391 individuals of South Asian descent, 4 of 12,016 individuals of African descent, 3 of 17,210 individuals of Latino descent, 1 of 12,895 individuals of Finnish descent and 3 of 3231 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.
Natera, Inc.	RCV000299112	SCV001452901	uncertain significance	Glycogen storage disease type III	2020-01-10	no assertion criteria provided	clinical testing