NM_000152.5(GAA):c.1192C>A (p.Leu398Met) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 3, 2022
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:: RCV001068891.5

Allele description [Variation Report for NM_000152.5(GAA):c.1192C>A (p.Leu398Met)]

NM_000152.5(GAA):c.1192C>A (p.Leu398Met)

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.1192C>A (p.Leu398Met)

HGVS:

NC_000017.11:g.80108605C>A
NG_009822.1:g.12050C>A
NM_000152.5:c.1192C>AMANE SELECT
NM_001079803.3:c.1192C>A
NM_001079804.3:c.1192C>A
NP_000143.2:p.Leu398Met
NP_001073271.1:p.Leu398Met
NP_001073272.1:p.Leu398Met
LRG_673t1:c.1192C>A
LRG_673:g.12050C>A
NC_000017.10:g.78082404C>A
NC_000017.10:g.78082404C>A
NM_000152.3:c.1192C>A

Protein change:

L398M

Links:

dbSNP: rs369707231

NCBI 1000 Genomes Browser:

rs369707231

Molecular consequence:

NM_000152.5:c.1192C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1192C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1192C>A - 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
SCV001234025	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001453422	Natera, Inc.	no assertion criteria provided	Uncertain significance (Mar 17, 2020)	germline	clinical testing
SCV001749752	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001234025

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 3, 2022)

germline

clinical testing

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

SCV001453422

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Mar 17, 2020)

germline

clinical testing

SCV001749752

GenomeConnect - Invitae Patient Insights Network

no classification provided

not provided

unknown

phenotyping only

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001234025.3

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 398 of the GAA protein (p.Leu398Met). This variant is present in population databases (rs369707231, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 862210). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Natera, Inc., SCV001453422.1

#	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 GenomeConnect - Invitae Patient Insights Network, SCV001749752.1

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

Description

Variant interpreted as Uncertain significance and reported on 04-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

#	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

Last Updated: May 1, 2024

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