rs1555599594

Variant names:

• chr17-80107579-CT-C
• rs1555599594
• NM_000152.5:c.716delT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4 PM2 PVS1

This summary comes from the ClinGen Evidence Repository: This variant, c.716delT (p.Leu239ArgfsTer29), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. One patient with this variant meets the ClinGen LSD VCEP’s specifications for PP4. This patient is compound heterozygous for the variant and c.1447G>A (p.Gly483Arg) (PMID 31606152, personal communication). This in trans data will be used in the assessment of p.Gly483Arg and is not included here in order to avoid circular logic. Another patient who is compound heterozygous for the variant has been reported (PMID 14695532). However, residual GAA activity was not provided and this data was not included. Therefore, PM3 is not currently met. This variant is not in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 556853, 2 star review status) with one submitter classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658795234/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 34)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.88
• Publications: 2 publications found

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.716delT	p.Leu239ArgfsTer29	frameshift_variant	Exon 4 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.716delT	p.Leu239ArgfsTer29	frameshift_variant	Exon 4 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4

Sep 20, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This variant, c.716delT (p.Leu239ArgfsTer29), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. One patient with this variant meets the ClinGen LSD VCEP's specifications for PP4. This patient is compound heterozygous for the variant and c.1447G>A (p.Gly483Arg) (PMID 31606152, personal communication). This in trans data will be used in the assessment of p.Gly483Arg and is not included here in order to avoid circular logic. Another patient who is compound heterozygous for the variant has been reported (PMID 14695532). However, residual GAA activity was not provided and this data was not included. Therefore, PM3 is not currently met. This variant is not in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 556853, 2 star review status) with one submitter classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. -

Dec 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556853). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type II (PMID: 14695532). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu239Argfs*29) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). -

Feb 21, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 20, 2019

Hadassah Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Nov 30, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in individuals with glycogen storage disease 2 (Hermans et al., 2004; Gupta et al., 2020); This variant is associated with the following publications: (PMID: 31254424, 31342611, 31606152, 14695532) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1555599594; hg19: chr17-78081378;