NM_000152.5(GAA):c.2783A>G (p.Tyr928Cys) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Dec 20, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001353145.8

Allele description [Variation Report for NM_000152.5(GAA):c.2783A>G (p.Tyr928Cys)]

NM_000152.5(GAA):c.2783A>G (p.Tyr928Cys)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.2783A>G (p.Tyr928Cys)

Other names:

NM_000152.5(GAA):c.2783A>G; p.Tyr928Cys

HGVS:

NC_000017.11:g.80118789A>G
NG_009822.1:g.22234A>G
NM_000152.5:c.2783A>GMANE SELECT
NM_001079803.3:c.2783A>G
NM_001079804.3:c.2783A>G
NP_000143.2:p.Tyr928Cys
NP_001073271.1:p.Tyr928Cys
NP_001073272.1:p.Tyr928Cys
LRG_673:g.22234A>G
NC_000017.10:g.78092588A>G
NM_000152.3:c.2783A>G
NM_000152.4:c.2783A>G
NM_000152.5:c.2783A>G

Protein change:

Y928C

Links:

dbSNP: rs1403885484

NCBI 1000 Genomes Browser:

rs1403885484

Molecular consequence:

NM_000152.5:c.2783A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.2783A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.2783A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Glycogen storage disease, type II (GSD2)
Synonyms:: ACID ALPHA-GLUCOSIDASE DEFICIENCY; GLYCOGENOSIS, GENERALIZED, CARDIAC FORM; GSD II; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009290; MedGen: C0017921; Orphanet: 365; OMIM: 232300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001547517	NxGen MDx	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 7, 2020)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31606152, 22252923, 25741868
SCV002112700	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22252923, 29122469, 31606152, 33301762, 33741225, 28492532
SCV004030051	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 21, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29122469, 33301762 Citation Link,
SCV004035128	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31606152, 25741868
SCV004227908	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Uncertain significance (Dec 20, 2023)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
South East Asian	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience.

Bali DS, Goldstein JL, Banugaria S, Dai J, Mackey J, Rehder C, Kishnani PS.

Am J Med Genet C Semin Med Genet. 2012 Feb 15;160C(1):40-9. doi: 10.1002/ajmg.c.31319. Epub 2012 Jan 17.

PubMed [citation]

PMID:: 22252923
PMCID:: PMC3278076

Late onset Pompe Disease in India - Beyond the Caucasian phenotype.

Puri RD, Setia N, N V, Jagadeesh S, Nampoothiri S, Gupta N, Muranjan M, Bhat M, Girisha KM, Kabra M, Verma J, Thomas DC, Biji I, Raja J, Makkar R, Verma IC, Kishnani PS.

Neuromuscul Disord. 2021 May;31(5):431-441. doi: 10.1016/j.nmd.2021.02.013. Epub 2021 Feb 16.

PubMed [citation]

PMID:: 33741225

See all PubMed Citations (7)

Details of each submission

From NxGen MDx, SCV001547517.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant c.2783A>G (p.Tyr928Cys) in GAA exon 19 maintains a polar side chain however, it is not found in gnomAD exomes (PM2) and consensus from in silico predictions supports a disruptive effect (PP3). This variant was first reported in Bali et al. PMID 22252923 in 2 cases and has been reported in 7 additional cases in a South Indian Infant-Onset Pompe Disease cohort in Gupta et al. PMID 31606152. We interpret c.2783A>G to be likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002112700.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 928 of the GAA protein (p.Tyr928Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 22252923, 29122469, 31606152, 33301762, 33741225). ClinVar contains an entry for this variant (Variation ID: 1048589). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004030051.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: GAA c.2783A>G (p.Tyr928Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250516 control chromosomes. c.2783A>G has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Example: Thomas_2021, Mori_2017). Additionally, the a-glucosidase activity in several homozygous patients is significantly reduced when compared to wildtype (Thomas_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29122469, 33301762). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV004035128.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	South East Asian	1	not provided	not provided	clinical testing	PubMed (2)
2	South East Asian	1	not provided	not provided	clinical testing	PubMed (2)
3	South East Asian	1	not provided	not provided	clinical testing	PubMed (2)
4	South East Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

The homozygous mis-sense variant c.2783A>G (p.Tyr928Cys) has been identified in a group of patients presented with symptoms like respiratory distress, cardiomegaly, ventilator support, muscle weakness, hypotonia, protuberant abdomen, hepatomegaly and feeding difficulties. The age of onset of symptoms ranged from at birth to 6 months. This has been previously reported PMID: 31606152

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV004227908.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000152.5:c.2783A>G in GAA is predicted to result in the substitution of tyrosine by cysteine at amino acid 928 (p.Tyr928Cys). The variant has been identified in at least four individuals (all Indian where the country of origin is known). One of these patients has symptoms consistent with late onset Pompe disease and documented laboratory values showing deficient GAA activity (PMID: 33741225) (PP4_Moderate). Three individuals are homozygous for the variant (PMID: 33301762, clinical diagnostic laboratory), and one individual is compound heterozygous for the variant and a variant of uncertain significance, c.2015G>T (p.Arg672Leu) (PMID: 29122469, 33741225). The allelic data for this patient will be used in the classification of p.Arg672Leu and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00003294 (3/91080 alleles) in the S. Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.664 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: : 1048589). In summary, this variant meets the criteria to be classified as a variant of unceratin significance for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel: PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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