1-99862297-A-G

Variant names:

• chr1-99862297-A-G
• rs147024351
• NM_000642.3:c.334A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000642.3(AGL):​c.334A>G​(p.Ile112Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000993 in 1,613,966 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 0.126
• Publications: 3 publications found

Genes affected

AGL (HGNC:321): (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) This gene encodes the glycogen debrancher enzyme which is involved in glycogen degradation. This enzyme has two independent catalytic activities which occur at different sites on the protein: a 4-alpha-glucotransferase activity and a amylo-1,6-glucosidase activity. Mutations in this gene are associated with glycogen storage disease although a wide range of enzymatic and clinical variability occurs which may be due to tissue-specific alternative splicing. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

AGL Gene-Disease associations (from GenCC):

• glycogen storage disease III

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019373447).
• BP6: Variant 1-99862297-A-G is Benign according to our data. Variant chr1-99862297-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 291324.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000605 (92/152146) while in subpopulation NFE AF = 0.00113 (77/68006). AF 95% confidence interval is 0.000928. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.334A>G	p.Ile112Val	missense_variant	Exon 4 of 34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.334A>G	p.Ile112Val	missense_variant	Exon 4 of 34	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000608 AC: 153 AN: 251480 AF XY: 0.000662

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00103 AC: 1511 AN: 1461820 Hom.: 7 Cov.: 31 AF XY: 0.00105 AC XY: 766 AN XY: 727212

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86256

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00124 AC: 1383 AN: 1111984

Other (OTH) AF: 0.000729 AC: 44 AN: 60390

GnomAD4 genome AF: 0.000605 AC: 92 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74386

African (AFR) AF: 0.000193 AC: 8 AN: 41498

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000931 Hom.: 0

Bravo AF: 0.000495

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.00131

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease type III Uncertain:4 Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 16, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 28, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Jan 10, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:2 Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGL: BP4

Dec 29, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 07, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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.

Inborn genetic diseases Uncertain:1

May 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.98
DANN	Benign	0.22
DEOGEN2	Benign	0.029	T;T;T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.77	T;.;.;.;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.019	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.22	N;N;N;N;.
PhyloP100		0.13
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.41	N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.29	T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T
Vest4		0.21
ClinPred		0.0052	T
GERP RS		-3.8
Varity_R		0.020
gMVP		0.31
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147024351; hg19: chr1-100327853;