NM_000152.5(GAA):c.2296T>C (p.Tyr766His) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 4, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003610604.2

Allele description [Variation Report for NM_000152.5(GAA):c.2296T>C (p.Tyr766His)]

NM_000152.5(GAA):c.2296T>C (p.Tyr766His)

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.2296T>C (p.Tyr766His)

HGVS:

NC_000017.11:g.80117074T>C
NG_009822.1:g.20519T>C
NM_000152.5:c.2296T>CMANE SELECT
NM_001079803.3:c.2296T>C
NM_001079804.3:c.2296T>C
NM_001406741.1:c.2296T>C
NM_001406742.1:c.2296T>C
NP_000143.2:p.Tyr766His
NP_000143.2:p.Tyr766His
NP_001073271.1:p.Tyr766His
NP_001073272.1:p.Tyr766His
NP_001393670.1:p.Tyr766His
NP_001393671.1:p.Tyr766His
LRG_673t1:c.2296T>C
LRG_673:g.20519T>C
LRG_673p1:p.Tyr766His
NC_000017.10:g.78090873T>C
NM_000152.3:c.2296T>C

Protein change:

Y766H

Molecular consequence:

NM_000152.5:c.2296T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.2296T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.2296T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406741.1:c.2296T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406742.1:c.2296T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004475612	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 4, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21605996, 22538254, 30564623, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004475612

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 4, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

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

Citations

PubMed

Expanding the clinical spectrum of late-onset Pompe disease: dilated arteriopathy involving the thoracic aorta, a novel vascular phenotype uncovered.

El-Gharbawy AH, Bhat G, Murillo JE, Thurberg BL, Kampmann C, Mengel KE, Kishnani PS.

Mol Genet Metab. 2011 Aug;103(4):362-6. doi: 10.1016/j.ymgme.2011.04.009. Epub 2011 May 5.

PubMed [citation]

PMID:: 21605996

The emerging phenotype of long-term survivors with infantile Pompe disease.

Prater SN, Banugaria SG, DeArmey SM, Botha EG, Stege EM, Case LE, Jones HN, Phornphutkul C, Wang RY, Young SP, Kishnani PS.

Genet Med. 2012 Sep;14(9):800-10. doi: 10.1038/gim.2012.44. Epub 2012 Apr 26.

PubMed [citation]

PMID:: 22538254
PMCID:: PMC3947503

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004475612.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr766 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21605996, 22538254, 30564623). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. This variant has not been reported in the literature in individuals affected with GAA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 766 of the GAA protein (p.Tyr766His).

#	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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