NM_000152.5(GAA):c.1445C>T (p.Pro482Leu) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Feb 7, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001261923.12

Allele description [Variation Report for NM_000152.5(GAA):c.1445C>T (p.Pro482Leu)]

NM_000152.5(GAA):c.1445C>T (p.Pro482Leu)

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.1445C>T (p.Pro482Leu)

Other names:

NM_000152.5(GAA):c.1445C>T; p.Pro482Leu

HGVS:

NC_000017.11:g.80110734C>T
NG_009822.1:g.14179C>T
NM_000152.5:c.1445C>TMANE SELECT
NM_001079803.3:c.1445C>T
NM_001079804.3:c.1445C>T
NP_000143.2:p.Pro482Leu
NP_001073271.1:p.Pro482Leu
NP_001073272.1:p.Pro482Leu
LRG_673:g.14179C>T
NC_000017.10:g.78084533C>T

Protein change:

P482L

Links:

dbSNP: rs2039212985

NCBI 1000 Genomes Browser:

rs2039212985

Molecular consequence:

NM_000152.5:c.1445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1445C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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histone deacetylase 2 isoform X2 [Cucumis sativus]
histone deacetylase 2 isoform X2 [Cucumis sativus]
gi|449447110|ref|XP_004141312.1|

Protein
PREDICTED: 4-coumarate--CoA ligase-like 5 [Cucumis melo]
PREDICTED: 4-coumarate--CoA ligase-like 5 [Cucumis melo]
gi|659104401|ref|XP_008452936.1|

Protein
Profile neighbors for GEO Profiles (Select 94361261) (199)
GEO Profiles
TGFB1I1 transforming growth factor beta 1 induced transcript 1 [Homo sapiens]
TGFB1I1 transforming growth factor beta 1 induced transcript 1 [Homo sapiens]
Gene ID:7041

Gene
Gene Links for GEO Profiles (Select 54955961) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001438057	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060049	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 16, 2021)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17616415, 31086307, 31931849, 33741225 Citation Link,
SCV002238325	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 20, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18425781, 29122469, 31392188, 17616415, 31086307, 28492532
SCV003852730	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Likely pathogenic (Feb 7, 2023)	germline	curation	Citation Link,
SCV005185110	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 22, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17616415, 31086307, 31931849, 33741225, 34530085 Citation Link

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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, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Southeast Asian	germline	yes	1	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

Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating.

Kroos M, Pomponio RJ, van Vliet L, Palmer RE, Phipps M, Van der Helm R, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2008 Jun;29(6):E13-26. doi: 10.1002/humu.20745.

PubMed [citation]

PMID:: 18425781

See all PubMed Citations (10)

Details of each submission

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV001438057.1

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

Description

The patient was presented Failure to thrive since 5 years of age diagnosed to have cardiomypopathy , hypotonia and weakness from 12 years of age, had muscle weakness and respiratory involvement was seen

Description

The variant c.1445C>T has been reported in Gort et. al. 2007 PMID: 17616415

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060049.2

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

Description

NM_000152.3(GAA):c.1445C>T(P482L) is a missense variant classified as likely pathogenic in the context of Pompe disease. P482L has been observed in cases with relevant disease (PMID: 31931849, 31086307, 17616415, 33741225, Cerón-Rodríguez_2014_(no PMID; article)). Functional assessments of this variant are not available in the literature. P482L has not been observed in population frequency databases. In summary, NM_000152.3(GAA):c.1445C>T(P482L) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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, SCV002238325.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant disrupts the p.Pro482 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18425781, 29122469, 31392188; Invitae). 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. 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: 982297). This missense change has been observed in individual(s) with Pompe disease (PMID: 17616415, 31086307). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 482 of the GAA protein (p.Pro482Leu).

#	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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV003852730.1

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

Description

The NM_000152.5:c.1445C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 482 (p.Pro482Leu). At least 5 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot, or were noted to have deficient GAA activity but results were not provided (PMID: 17616415, 31086307, 34530085, 33741225, 31931849) (PP4_Moderate). Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (p.Asp404Asn, p.Asn87Glnfs*9) (PMID: 31086307, 31931849). One individual was homozygous for the variant (PMID: 33741225) (PM3). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.918 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.1445C>G (p.Pro482Arg) (PMID: 31392188, 22644586, ClinVar Variation ID 1067574) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 982297; 2 star review status) with two submitters classifying the variant as pathogenic, and two as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PP4_Moderate, PM3, PP3, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen LSD VCEP, February 7, 2023).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005185110.1

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

Description

Variant summary: GAA c.1445C>T (p.Pro482Leu) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, TIM barrel domain (IPR000322) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250910 control chromosomes. c.1445C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in the homozygous or compound heterozygous state (Aminoso_2022, Bevilacqua_2020, Gort_2007, Kishnani_2019, Puri_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34530085, 31931849, 17616415, 31086307, 33741225). ClinVar contains an entry for this variant (Variation ID: 982297). Based on the evidence outlined above, the variant was 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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