1-99916709-C-T

Position:

chr1-99916709-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000642.3(AGL):c.4459C>T(p.Arg1487Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

AGL
NM_000642.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.40

Variant links:

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 links:

LOC124904230 (HGNC:):

LOC124904230 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0304 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-99916709-C-T is Pathogenic according to our data. Variant chr1-99916709-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 456508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3 linkuse as main transcript	c.4459C>T	p.Arg1487Ter	stop_gained	33/34	ENST00000361915.8	NP_000633.2
LOC124904230	XR_007066249.1 linkuse as main transcript	n.1146-3492G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8 linkuse as main transcript	c.4459C>T	p.Arg1487Ter	stop_gained	33/34	1	NM_000642.3	ENSP00000355106	P1	P35573-1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250906

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460986

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726800

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000222

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease type III

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	This sequence change creates a premature translational stop signal (p.Arg1487) in the AGL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the AGL protein. This variant is present in population databases (rs12118058, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type III (PMID: 29374762). ClinVar contains an entry for this variant (Variation ID: 456508). This variant disrupts a region of the AGL protein in which other variant(s) (p.Tyr1510) have been determined to be pathogenic (PMID: 8990006, 20071996, 20490926, 23430490). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2024	Variant summary: AGL c.4459C>T (p.Arg1487X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. This variant is not anticipated to result in nonsense mediated decay, however variants downstream from this position have been classified pathogenic internally or in ClinVar (CV IDS:1094, 656738). The variant allele was found at a frequency of 3.6e-05 in 250906 control chromosomes (gnomAD). c.4459C>T has been reported in the literature in a compound heterozygous individual affected with Glycogen Storage Disease (example: Quackenbush_2018). The following publications have been ascertained in the context of this evaluation (PMID: 31980526, 17994282, 29374762). ClinVar contains an entry for this variant (Variation ID: 456508). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 16, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 23, 2023	- -

Glycogen storage disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 10, 2018

The p.Arg1487X variant in AGL has been reported in the compound heterozygous sta te in 1 individual with glycogen storage disorder type III (GSDIII; Quackenbush 2016). It has also been identified in 2/24018 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12118058 ), which is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 1487. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated p rotein. Many other truncating variants, which are also predicted to escape NMD a nd located in this region of the AGL gene, have been reported in affected indivi duals with deficient enzyme activity, suggesting that the carboxy terminus is es sential for normal enzyme function (Parvari 1997, Shen 1997, Rousseau-Nepton 201 5, Lu 2016). In summary, although additional studies are required to fully estab lish its clinical significance, the p.Arg1487X variant is likely pathogenic. ACM G/AMP Criteria applied: PVS1_Strong, PM3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

Vest4

0.92

GERP RS

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over