NM_000152.5(GAA):c.1001G>A (p.Gly334Asp) AND Glycogen storage disease, type II

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 27, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001261939.4

Allele description [Variation Report for NM_000152.5(GAA):c.1001G>A (p.Gly334Asp)]

NM_000152.5(GAA):c.1001G>A (p.Gly334Asp)

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.1001G>A (p.Gly334Asp)

HGVS:

NC_000017.11:g.80108335G>A
NG_009822.1:g.11780G>A
NM_000152.5:c.1001G>AMANE SELECT
NM_001079803.3:c.1001G>A
NM_001079804.3:c.1001G>A
NP_000143.2:p.Gly334Asp
NP_001073271.1:p.Gly334Asp
NP_001073272.1:p.Gly334Asp
LRG_673:g.11780G>A
NC_000017.10:g.78082134G>A

Protein change:

G334D

Links:

dbSNP: rs2039143109

NCBI 1000 Genomes Browser:

rs2039143109

Molecular consequence:

NM_000152.5:c.1001G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1001G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1001G>A - 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

Recent activity

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putative chondrosarcoma-associated gene 1 protein [Homo sapiens]
putative chondrosarcoma-associated gene 1 protein [Homo sapiens]
gi|24234760|ref|NP_705611.1|

Protein
Rattus norvegicus very low density lipoprotein receptor (Vldlr), mRNA
Rattus norvegicus very low density lipoprotein receptor (Vldlr), mRNA
gi|6981705|ref|NM_013155.1|

Nucleotide
Homo sapiens telomerase reverse transcriptase (TERT), transcript variant 3, mRNA
Homo sapiens telomerase reverse transcriptase (TERT), transcript variant 3, mRNA
gi|38201697|ref|NM_198253.1|

Nucleotide
Mus musculus predicted gene 15511 (Gm15511), long non-coding RNA
Mus musculus predicted gene 15511 (Gm15511), long non-coding RNA
gi|1027860953|ref|NR_136934.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001438060	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004653601	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21687968, 33741225, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001438060

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 15, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004653601

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 27, 2023)

germline

clinical testing

PubMed (3)
[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
southeast asian	germline	yes	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Urine analysis of glucose tetrasaccharide by HPLC; a useful marker for the investigation of patients with Pompe and other glycogen storage diseases.

Manwaring V, Prunty H, Bainbridge K, Burke D, Finnegan N, Franses R, Lam A, Vellodi A, Heales S.

J Inherit Metab Dis. 2012 Mar;35(2):311-6. doi: 10.1007/s10545-011-9360-2. Epub 2011 Jun 18. Erratum in: J Inherit Metab Dis. 2012 Mar;35(2):369.

PubMed [citation]

PMID:: 21687968

See all PubMed Citations (4)

Details of each submission

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV001438060.1

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

Description

Patient 17, female was presented with Proximal muscle weakness wqith age on onset is 17yrs. Patient 18, male was presented with Proximal Muscle weakness & the age of onset was 21yrs.

Description

The variant c.1001G>A is likely pathogenic based on phenotype of the patient & ACMG guidelines

#	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		2	not provided	2	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004653601.1

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly334 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 21687968), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 982365). This missense change has been observed in individual(s) with Pompe disease (PMID: 33741225). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 334 of the GAA protein (p.Gly334Asp).

#	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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