NM_000152.5(GAA):c.2253C>T (p.Leu751=) AND Glycogen storage disease, type II

Germline classification:: Likely benign (4 submissions)
Last evaluated:: Jan 21, 2024
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:: RCV001080332.15

Allele description [Variation Report for NM_000152.5(GAA):c.2253C>T (p.Leu751=)]

NM_000152.5(GAA):c.2253C>T (p.Leu751=)

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.2253C>T (p.Leu751=)

HGVS:

NC_000017.11:g.80117031C>T
NG_009822.1:g.20476C>T
NM_000152.5:c.2253C>TMANE SELECT
NM_001079803.3:c.2253C>T
NM_001079804.3:c.2253C>T
NP_000143.2:p.Leu751=
NP_001073271.1:p.Leu751=
NP_001073272.1:p.Leu751=
LRG_673t1:c.2253C>T
LRG_673:g.20476C>T
NC_000017.10:g.78090830C>T
NM_000152.3:c.2253C>T
NM_000152.4(GAA):c.2253C>T
p.Leu751=

Links:

dbSNP: rs140441758

NCBI 1000 Genomes Browser:

rs140441758

Molecular consequence:

NM_000152.5:c.2253C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001079803.3:c.2253C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001079804.3:c.2253C>T - synonymous variant - [Sequence Ontology: SO:0001819]

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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Handroanthus impetiginosus isolate UFG-1 CDL12_scaffold3079, whole genome shotgun sequence
gi|1276252485|gb|NKXS01003078.1||gn :NKXS01|CDL12_scaffold3079

Nucleotide
Handroanthus impetiginosus isolate UFG-1 CDL12_scaffold3147, whole genome shotgu...
Handroanthus impetiginosus isolate UFG-1 CDL12_scaffold3147, whole genome shotgun sequence
gi|1276252229|gb|NKXS01003146.1||gn :NKXS01|CDL12_scaffold3147

Nucleotide
Handroanthus impetiginosus isolate UFG-1 CDL12_scaffold3117, whole genome shotgu...
Handroanthus impetiginosus isolate UFG-1 CDL12_scaffold3117, whole genome shotgun sequence
gi|1276252323|gb|NKXS01003116.1||gn :NKXS01|CDL12_scaffold3117

Nucleotide
CBTA4655.fwd NICHD_XGC_tropPanc1 Xenopus tropicalis cDNA clone IMAGE:8877301 5',...
CBTA4655.fwd NICHD_XGC_tropPanc1 Xenopus tropicalis cDNA clone IMAGE:8877301 5', mRNA sequence
gi|129344709|gnl|dbEST|45163837|gb| 197.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000626556	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 21, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001422780	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jan 22, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001810184	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002092119	Natera, Inc.	no assertion criteria provided	Likely benign (Feb 24, 2021)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000626556.7

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

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422780.2

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

Description

The c.2253C>T (p.Leu751=) variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS by EGL Genetic Diagnostics and a likely benign variant by Invitae in ClinVar (Variation ID: 290924). This variant has been identified in 0.024% (6/24918) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140441758). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: PM2, BP4, BP7 (Richards 2015).

#	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 Genome-Nilou Lab, SCV001810184.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002092119.1

#	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

Last Updated: Sep 29, 2024

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