NM_000152.5(GAA):c.1240T>C (p.Phe414Leu) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 12, 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:: RCV001855124.6

Allele description [Variation Report for NM_000152.5(GAA):c.1240T>C (p.Phe414Leu)]

NM_000152.5(GAA):c.1240T>C (p.Phe414Leu)

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.1240T>C (p.Phe414Leu)

HGVS:

NC_000017.11:g.80108742T>C
NG_009822.1:g.12187T>C
NM_000152.5:c.1240T>CMANE SELECT
NM_001079803.3:c.1240T>C
NM_001079804.3:c.1240T>C
NP_000143.2:p.Phe414Leu
NP_001073271.1:p.Phe414Leu
NP_001073272.1:p.Phe414Leu
LRG_673:g.12187T>C
NC_000017.10:g.78082541T>C

Protein change:

F414L

Links:

dbSNP: rs886042630

NCBI 1000 Genomes Browser:

rs886042630

Molecular consequence:

NM_000152.5:c.1240T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1240T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1240T>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
SCV002115684	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 12, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30564623, 31342611, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002115684

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 12, 2022)

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

Citations

PubMed

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.

Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider T, da Silva C, Beadling R, Alexander JJ, Askree SH, Whitt Z, Bean L, Collins C, Khadilkar S, Gaitonde P, Dastur R, Wicklund M, Mozaffar T, Harms M, Rufibach L, Mittal P, Hegde M.

Ann Clin Transl Neurol. 2018 Dec;5(12):1574-1587. doi: 10.1002/acn3.649.

PubMed [citation]

PMID:: 30564623
PMCID:: PMC6292381

GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry.

Reuser AJJ, van der Ploeg AT, Chien YH, Llerena J Jr, Abbott MA, Clemens PR, Kimonis VE, Leslie N, Maruti SS, Sanson BJ, Araujo R, Periquet M, Toscano A, Kishnani PS, On Behalf Of The Pompe Registry Sites.

Hum Mutat. 2019 Nov;40(11):2146-2164. doi: 10.1002/humu.23878. Epub 2019 Aug 7.

PubMed [citation]

PMID:: 31342611
PMCID:: PMC6852536

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002115684.3

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

Description

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. 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: 283455). This missense change has been observed in individual(s) with late onset Pompe disease (PMID: 30564623, 31342611). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 414 of the GAA protein (p.Phe414Leu).

#	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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