NM_000152.5(GAA):c.1456G>C (p.Ala486Pro) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Oct 30, 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:: RCV003461594.3

Allele description [Variation Report for NM_000152.5(GAA):c.1456G>C (p.Ala486Pro)]

NM_000152.5(GAA):c.1456G>C (p.Ala486Pro)

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.1456G>C (p.Ala486Pro)

HGVS:

NC_000017.11:g.80110745G>C
NG_009822.1:g.14190G>C
NG_137935.1:g.1035G>C
NM_000152.5:c.1456G>CMANE SELECT
NM_001079803.3:c.1456G>C
NM_001079804.3:c.1456G>C
NM_001406741.1:c.1456G>C
NM_001406742.1:c.1456G>C
NP_000143.2:p.Ala486Pro
NP_000143.2:p.Ala486Pro
NP_001073271.1:p.Ala486Pro
NP_001073272.1:p.Ala486Pro
NP_001393670.1:p.Ala486Pro
NP_001393671.1:p.Ala486Pro
LRG_673t1:c.1456G>C
LRG_673:g.14190G>C
LRG_673p1:p.Ala486Pro
NC_000017.10:g.78084544G>C
NM_000152.3:c.1456G>C

Protein change:

A486P

Molecular consequence:

NM_000152.5:c.1456G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1456G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1456G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406741.1:c.1456G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406742.1:c.1456G>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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004195423	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 30, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004296872	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19588081, 22644586, 26350092, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004195423

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 30, 2023)

unknown

clinical testing

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

SCV004296872

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 21, 2023)

germline

clinical testing

PubMed (4)
[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
not provided	unknown	unknown	not provided	not provided	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

Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations.

Oba-Shinjo SM, da Silva R, Andrade FG, Palmer RE, Pomponio RJ, Ciociola KM, S Carvalho M, Gutierrez PS, Porta G, Marrone CD, Munoz V, Grzesiuk AK, Llerena JC Jr, Berditchevsky CR, Sobreira C, Horovitz D, Hatem TP, Frota ER, Pecchini R, Kouyoumdjian JA, Werneck L, Amado VM, et al.

J Neurol. 2009 Nov;256(11):1881-90. doi: 10.1007/s00415-009-5219-y. Epub 2009 Jul 9.

PubMed [citation]

PMID:: 19588081

See all PubMed Citations (5)

Details of each submission

From Baylor Genetics, SCV004195423.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004296872.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). 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. This missense change has been observed in individuals with Pompe disease (PMID: 19588081, 22644586, 26350092). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 486 of the GAA protein (p.Ala486Pro).

#	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

ClinVar

Relating variation to medicine