NM_000152.5(GAA):c.701C>T (p.Thr234Met) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 15, 2024
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:: RCV001832749.5

Allele description [Variation Report for NM_000152.5(GAA):c.701C>T (p.Thr234Met)]

NM_000152.5(GAA):c.701C>T (p.Thr234Met)

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.701C>T (p.Thr234Met)

HGVS:

NC_000017.11:g.80107565C>T
NG_009822.1:g.11010C>T
NM_000152.5:c.701C>TMANE SELECT
NM_001079803.3:c.701C>T
NM_001079804.3:c.701C>T
NP_000143.2:p.Thr234Met
NP_001073271.1:p.Thr234Met
NP_001073272.1:p.Thr234Met
LRG_673t1:c.701C>T
LRG_673:g.11010C>T
NC_000017.10:g.78081364C>T
NM_000152.3:c.701C>T

Protein change:

T234M

Links:

dbSNP: rs752054011

NCBI 1000 Genomes Browser:

rs752054011

Molecular consequence:

NM_000152.5:c.701C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.701C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.701C>T - 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

Recent activity

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Homo sapiens kringle containing transmembrane protein 2 (KREMEN2), transcript va...
Homo sapiens kringle containing transmembrane protein 2 (KREMEN2), transcript variant 2, mRNA
gi|27437002|ref|NM_024507.2|

Nucleotide
PREDICTED: receptor homology region, transmembrane domain- and RING domain-conta...
PREDICTED: receptor homology region, transmembrane domain- and RING domain-containing protein 5-like [Rhinolophus sinicus]
gi|1124038523|ref|XP_019577476.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002091953	Natera, Inc.	no assertion criteria provided	Uncertain significance (Mar 19, 2020)	germline	clinical testing
SCV002152029	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 36310651, 22644586, 22676651, 34852371, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002091953

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Mar 19, 2020)

germline

clinical testing

SCV002152029

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 15, 2024)

germline

clinical testing

PubMed (5)
[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

Newborn screening for Pompe disease in Italy: Long-term results and future challenges.

Gragnaniello V, Pijnappel PWWM, Burlina AP, In 't Groen SLM, Gueraldi D, Cazzorla C, Maines E, Polo G, Salviati L, Di Salvo G, Burlina AB.

Mol Genet Metab Rep. 2022 Dec;33:100929. doi: 10.1016/j.ymgmr.2022.100929.

PubMed [citation]

PMID:: 36310651
PMCID:: PMC9597184

Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants.

Kroos M, Hoogeveen-Westerveld M, Michelakakis H, Pomponio R, Van der Ploeg A, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2012 Aug;33(8):1161-5. doi: 10.1002/humu.22108. Epub 2012 May 29.

PubMed [citation]

PMID:: 22644586

See all PubMed Citations (5)

Details of each submission

From Natera, Inc., SCV002091953.1

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002152029.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 234 of the GAA protein (p.Thr234Met). This variant is present in population databases (rs752054011, gnomAD 0.003%). This missense change has been observed in individual(s) with Pompe disease (PMID: 36310651). ClinVar contains an entry for this variant (Variation ID: 1190471). 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 with a positive predictive value of 95%. This variant disrupts the p.Thr234 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22644586, 22676651, 34852371). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: Sep 29, 2024

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