ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.307T>G (p.Cys103Gly)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000152.5(GAA):c.307T>G (p.Cys103Gly)
Variation ID: 92483 Accession: VCV000092483.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80104893 (GRCh38) [ NCBI UCSC ] 17: 78078692 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 24, 2015 Apr 20, 2024 Sep 21, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.307T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Cys103Gly missense NM_001079803.2:c.307T>G NM_001079803.3:c.307T>G NP_001073271.1:p.Cys103Gly missense NM_001079804.3:c.307T>G NP_001073272.1:p.Cys103Gly missense NC_000017.11:g.80104893T>G NC_000017.10:g.78078692T>G NG_009822.1:g.8338T>G LRG_673:g.8338T>G LRG_673t1:c.307T>G LRG_673p1:p.Cys103Gly P10253:p.Cys103Gly - Protein change
- C103G
- Other names
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- Canonical SPDI
- NC_000017.11:80104892:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00003
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 | ||
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HI score
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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. |
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GAA | - | - |
GRCh38 GRCh38 GRCh37 |
2757 | 2807 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000078179.24 | |
Pathogenic (8) |
reviewed by expert panel
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Sep 21, 2022 | RCV000811478.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 23, 2015 | RCV004017390.1 |
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. |
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Pathogenic
(Sep 21, 2022)
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reviewed by expert panel
Method: curation
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
Accession: SCV002817442.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
Comment:
The NM_000152.5: c.307T>G variant in GAA is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 103 (p.Cys103Gly). This variant … (more)
The NM_000152.5: c.307T>G variant in GAA is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 103 (p.Cys103Gly). This variant has been reported in at least 12 patients who have been diagnosed with Pompe disease, including patients with documented GAA deficiency in the affected range in dried blood spot, leukocytes, and fibroblasts and <10% normal GAA activity in muscle (PMIDs: 16838077, 18285536, 21109266, 22676651, 24011652, 24158270, 29803406; Pediatr Pol 2021; 96 (3): 220–222; https://doi.org/10.5114/polp.2021.109310) and three on enzyme replacement therapy (PMID: 18607768, 29565424, 29803406, 23160972) (PP4_Moderate). Of note, in some of these patients, the variant was noted to be in cis with another variant (p.Asp91Asn) which can falsely lower GAA activity in in vitro assays when the substrate is glycogen, but not when the substrate is an artificial substrate, 4-MU. This was taken into account when utilizing GAA activity data. Of the reported patients, at least 11 patients compound heterozygous for the variant, phase unknown, and a known pathogenic variant in GAA including c.-32-13T>G (9 patients, PMID: 16838077, 18285536, 18607768, 21109266, 22676651, 23160972, 24011652, 24158270, 29803406; Pediatr Pol 2021; 96 (3): 220–222; https://doi.org/10.5114/polp.2021.109310), c.525delT (PMID: 14695532) and c.2481+102_c.2646+31del (PMID: 29565424). In addition, one patient is compound heterozygous for the variant and c.1465G>A (p.Asp489Asn) (PMID: 18429042). The allelic data from this patient will be used in the assessment of p.Asp489Asn and is not included here to avoid circular logic. For another patient, the cDNA change for the variants was not provided and therefore the data was not included (PMID: 28196920). The highest population minor allele frequency in gnomAD is 0.00001 (1/126998 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant resulted in 1.5% normal activity, and evidence of abnormal GAA processing on Western blot (PMID: 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.985 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other amino acid substitutions at the same position have been reported in patients with Pompe disease - c.307T>C (p.Cys103Arg) (PMIDs 21984055, 22644586) and c.309C>G (p.Cys103Trp) (PMID 27142047); the classification of p.Cys103Gly will be used to support the classification of these other variants. Therefore, the data is not used here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 92483, 2 star review status) with 8 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Approved by the ClinGen LSD VCEP on Sept. 21, 2022). (less)
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Pathogenic
(Jul 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950047.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
This variant was identified in trans as compound heterozygous with NM_000152.5:c.-32-13T>G.
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Likely pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001423069.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The heterozygous p.Cys103Gly variant in GAA has been reported in 13 individuals (including 8 Germans, 1 Australian, 1 Greek and 1 Italian individuals) with Glycogen … (more)
The heterozygous p.Cys103Gly variant in GAA has been reported in 13 individuals (including 8 Germans, 1 Australian, 1 Greek and 1 Italian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 14695532, 22676651, 16838077, 23160972, 18607768, 18429042, 17643989, 24158270, 29565424, 18285536, 28196920), and has also been reported pathogenic by EGL Genetic Diagnostics, Invitae, and GeneDx in ClinVar (Variation ID: 92483). This variant has been identified in 0.006% (1/15414) of European (non-Finnish) chromosome by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123174). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Cys103Gly variant may impact GAA protein processing and activity (PMID: 14695532). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a pathogenic variant and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Cys103Gly variant is pathogenic (PMID: 16838077, 24158270, 20033296, 28196920, 22676651, 18285536). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 16838077, 24158270, 20033296, 28196920, 22676651, 18285536). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Supporting, PS3, PM2, PP3, PP4 (Richards 2015). (less)
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Pathogenic
(Feb 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502991.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
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Likely pathogenic
(Oct 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809705.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004197796.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021199.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000951746.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 103 of the GAA protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 103 of the GAA protein (p.Cys103Gly). This variant is present in population databases (rs398123174, gnomAD 0.0008%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 14695532, 18429042, 18607768, 21109266, 24158270, 29181627). ClinVar contains an entry for this variant (Variation ID: 92483). 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%. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004811748.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
GAA: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Dec 23, 2015)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847980.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Cys103Gly variant in GAA has been reported in 7 individuals with glycogen storage disease II, all of whom were compound heterozygous with a second … (more)
The p.Cys103Gly variant in GAA has been reported in 7 individuals with glycogen storage disease II, all of whom were compound heterozygous with a second pathogenic GAA variant (Hermans 2004, Kroos 2007, Joshi 2008, Fidzianska 2011, Remiche 2014). This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Cys103Gly variant may impact protein function (Hermans 2004). In summary, this variant meets our criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based upon absence from controls and multiple occurrences with pathogenic GAA variants in individuals with glycogen storage disease II. (less)
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Pathogenic
(Nov 14, 2012)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000227028.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(May 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361271.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: GAA c.307T>G (p.Cys103Gly) results in a non-conservative amino acid change located in the P-type trefoil domain (IPR000519) of the encoded protein sequence. Five … (more)
Variant summary: GAA c.307T>G (p.Cys103Gly) results in a non-conservative amino acid change located in the P-type trefoil domain (IPR000519) 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 248096 control chromosomes (gnomAD). c.307T>G has been reported in the literature in multiple individuals affected with late onset and infantile forms of Pompe Disease (e.g. Hermans_2004, Remiche_2014). These data indicate that the variant is very likely to be associated with disease. Experimental evidence from an in vitro study reports greater than 98% loss of enzymatic activity (Hermans_2004) for this variant. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322396.8
First in ClinVar: Mar 24, 2015 Last updated: May 13, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant leads to approximately 98% loss of lysosomal alpha … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant leads to approximately 98% loss of lysosomal alpha glucosidase activity (Hermans et al., 2004); Located in the Trefoil Type-P Domain (Kroos et al., 2012; Sugawara et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24158270, 27189384, 27142047, 31254424, 21109266, 18429042, 29181627, 31301153, 31086307, 30105547, 33560568, 22253258, 19343043, 34852371, 14695532, 18607768) (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease type II
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453581.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening. | de Faria DOS | Human mutation | 2021 | PMID: 33560568 |
Assessment of the functional impact on the pre-mRNA splicing process of 28 nucleotide variants associated with Pompe disease in GAA exon 2 and their recovery using antisense technology. | Goina E | Human mutation | 2019 | PMID: 31301153 |
Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease. | Kishnani PS | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31086307 |
Genetic basis of hypertrophic cardiomyopathy in children. | Rupp S | Clinical research in cardiology : official journal of the German Cardiac Society | 2019 | PMID: 30105547 |
Pompe disease in Austria: clinical, genetic and epidemiological aspects. | Löscher WN | Journal of neurology | 2018 | PMID: 29181627 |
Effect of enzyme replacement therapy on isokinetic strength for all major muscle groups in four patients with Pompe disease-a long-term follow-up. | Andreassen CS | Molecular genetics and metabolism | 2014 | PMID: 24685124 |
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 |
Respiratory function in late-onset Pompe disease patients receiving long-term enzyme replacement therapy for more than 48 months. | Schneider I | Wiener medizinische Wochenschrift (1946) | 2013 | PMID: 23160972 |
A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations. | Herzog A | Orphanet journal of rare diseases | 2012 | PMID: 22676651 |
Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants. | Kroos M | Human mutation | 2012 | PMID: 22644586 |
Late form of Pompe disease with glycogen storage in peripheral nerves axons. | Fidziańska A | Journal of the neurological sciences | 2011 | PMID: 21109266 |
Molecular diagnosis of German patients with late-onset glycogen storage disease type II. | Joshi PR | Journal of inherited metabolic disease | 2008 | PMID: 18607768 |
Molecular and functional characterization of eight novel GAA mutations in Italian infants with Pompe disease. | Pittis MG | Human mutation | 2008 | PMID: 18429042 |
Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients. | Müller-Felber W | Neuromuscular disorders : NMD | 2007 | PMID: 17643989 |
Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype. | Kroos MA | Neurology | 2007 | PMID: 17210890 |
Seven cases of Pompe disease from Greece. | Kroos M | Journal of inherited metabolic disease | 2006 | PMID: 16838077 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4e54404c-9474-4131-8b11-2a8f862e3e64 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e5afb18d-a245-421a-9d32-466c06f390cf | - | - | - | - |
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Text-mined citations for rs398123174 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.