VCV002977309.1 - ClinVar

NM_000152.5(GAA):c.1654C>T (p.Leu552Phe)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000152.5(GAA):c.1654C>T (p.Leu552Phe)

Variation ID: 2977309 Accession: VCV002977309.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q25.3 17: 80112000 (GRCh38) [ NCBI UCSC ] 17: 78085799 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 29, 2024	Feb 28, 2024	Nov 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000152.5:c.1654C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000143.2:p.Leu552Phe	missense
NM_001079803.3:c.1654C>T	NP_001073271.1:p.Leu552Phe	missense
NM_001079804.3:c.1654C>T	NP_001073272.1:p.Leu552Phe	missense
NM_001406741.1:c.1654C>T	NP_001393670.1:p.Leu552Phe	missense
NM_001406742.1:c.1654C>T	NP_001393671.1:p.Leu552Phe	missense
NC_000017.11:g.80112000C>T
NC_000017.10:g.78085799C>T
NG_009822.1:g.15445C>T
LRG_673:g.15445C>T
LRG_673t1:c.1654C>T	LRG_673p1:p.Leu552Phe

... more HGVS ... less HGVS

Protein change

L552F

Other names

Canonical SPDI

NC_000017.11:80111999:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GAA		-	-	GRCh38 GRCh38 GRCh37	2805	2857

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Glycogen storage disease, type II	Likely pathogenic (1)	criteria provided, single submitter	Nov 22, 2023	RCV003831427.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Nov 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease, type II Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004635850.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (12) PubMed: 14695532‚ 17213836‚ 17616415‚ 18607768‚ 19588081‚ 19862843‚ 20638881‚ 24158270‚ 25036864‚ 25409744‚ 25681614‚ 27666774 Comment: This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 552 of the GAA protein (p.Leu552Phe). … (more) This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 552 of the GAA protein (p.Leu552Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GAA-related conditions. 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 with a positive predictive value of 95%. This variant disrupts the p.Leu552 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14695532, 17213836, 17616415, 18607768, 19588081, 19862843, 20638881, 24158270, 25036864, 25409744, 25681614, 27666774). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. (less)

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 552 of the GAA protein (p.Leu552Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GAA-related conditions. 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 with a positive predictive value of 95%. This variant disrupts the p.Leu552 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14695532, 17213836, 17616415, 18607768, 19588081, 19862843, 20638881, 24158270, 25036864, 25409744, 25681614, 27666774). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The frequency of late-onset Pompe disease in pediatric patients with limb-girdle muscle weakness and nonspecific hyperCKemia: A multicenter study.	Ünver O	Neuromuscular disorders : NMD	2016	PMID: 27666774
Novel GAA mutations in patients with Pompe disease.	Turaça LT	Gene	2015	PMID: 25681614
Enzyme enhancers for the treatment of Fabry and Pompe disease.	Lukas J	Molecular therapy : the journal of the American Society of Gene Therapy	2015	PMID: 25409744
The pharmacological chaperone AT2220 increases the specific activity and lysosomal delivery of mutant acid alpha-glucosidase, and promotes glycogen reduction in a transgenic mouse model of Pompe disease.	Khanna R	PloS one	2014	PMID: 25036864
Extended phenotype description and new molecular findings in late onset glycogen storage disease type II: a northern Italy population study and review of the literature.	Remiche G	Journal of neurology	2014	PMID: 24158270
Pompe disease: dramatic improvement in gastrointestinal function following enzyme replacement therapy. A report of three later-onset patients.	Bernstein DL	Molecular genetics and metabolism	2010	PMID: 20638881
The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase.	Flanagan JJ	Human mutation	2009	PMID: 19862843
Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations.	Oba-Shinjo SM	Journal of neurology	2009	PMID: 19588081
Molecular diagnosis of German patients with late-onset glycogen storage disease type II.	Joshi PR	Journal of inherited metabolic disease	2008	PMID: 18607768
Glycogen storage disease type II in Spanish patients: high frequency of c.1076-1G>C mutation.	Gort L	Molecular genetics and metabolism	2007	PMID: 17616415
Pharmacological enhancement of mutated alpha-glucosidase activity in fibroblasts from patients with Pompe disease.	Parenti G	Molecular therapy : the journal of the American Society of Gene Therapy	2007	PMID: 17213836
Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II.	Hermans MM	Human mutation	2004	PMID: 14695532
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Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000152.5(GAA):c.1654C>T (p.Leu552Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...