ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.569G>A (p.Arg190His)
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.569G>A (p.Arg190His)
Variation ID: 188809 Accession: VCV000188809.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80105771 (GRCh38) [ NCBI UCSC ] 17: 78079570 (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 29, 2015 Jun 17, 2024 Feb 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.569G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Arg190His missense NM_001079803.3:c.569G>A NP_001073271.1:p.Arg190His missense NM_001079804.3:c.569G>A NP_001073272.1:p.Arg190His missense NC_000017.11:g.80105771G>A NC_000017.10:g.78079570G>A NG_009822.1:g.9216G>A LRG_673:g.9216G>A LRG_673t1:c.569G>A P10253:p.Arg190His - Protein change
- R190H
- Other names
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- Canonical SPDI
- NC_000017.11:80105770:G:A
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
2793 | 2844 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Feb 22, 2024 | RCV000169143.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 31, 2023 | RCV003144146.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 14, 2023 | RCV004020013.1 |
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
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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
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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
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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
(Apr 02, 2018)
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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: SCV000919379.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: GAA c.569G>A (p.Arg190His) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel of the encoded protein sequence. Five … (more)
Variant summary: GAA c.569G>A (p.Arg190His) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 1.6e-05 in 244686 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (1.6e-05 vs 0.0042), allowing no conclusion about variant significance. The variant, c.569G>A, has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(May 31, 2014)
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criteria provided, single submitter
Method: literature only
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220363.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Feb 22, 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:
unknown
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Baylor Genetics
Accession: SCV004197869.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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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: SCV001422620.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Arg190His variant in GAA has been reported in 2 Dutch and 1 Taiwanese individuals with Glycogen Storage Disease II, segregated with disease in 2 … (more)
The p.Arg190His variant in GAA has been reported in 2 Dutch and 1 Taiwanese individuals with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 23000108, 24444888), and has also been reported likely pathogenic by Counsyl and pathogenic by Integrated Genetics in ClinVar (Variation ID: 188809). This variant has been identified in 0.006% (1/16218) of African chromosomes, 0.006% (2/34578) of Latino chromosomes, and 0.001% (1/113436) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs528367092). 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 provide some evidence that the p.Arg190His variant may impact GAA activity and proteolytically activated GAA levels (PMID: 22644586). 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. One species (scarlet macaw) carries a Histidine (His) at this position, raising the possibility that this change at this position may be tolerated. However, the presence of this variant in combination with pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg190His variant is pathogenic (PMID: 23000108, 24444888). The phenotype of 3 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity assay results in fibroblasts or a dried blood spot (PMID: 23000108, 24444888). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PP3, PM2, PP4, PM3_Supporting (Richards 2015). (less)
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Likely pathogenic
(Sep 01, 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: SCV002809766.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jul 31, 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: SCV003834105.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 30, 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: SCV001226092.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 190 of the GAA protein (p.Arg190His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 190 of the GAA protein (p.Arg190His). This variant is present in population databases (rs528367092, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21484825, 23000108, 24444888, 29149851, 31076647). ClinVar contains an entry for this variant (Variation ID: 188809). 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.Arg190 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 29046207), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV005032509.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The p.R190H variant (also known as c.569G>A), located in coding exon 2 of the GAA gene, results from a G to A substitution at nucleotide … (more)
The p.R190H variant (also known as c.569G>A), located in coding exon 2 of the GAA gene, results from a G to A substitution at nucleotide position 569. The arginine at codon 190 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in individuals with Pompe disease who were compound heterozygous with additional alterations in GAA (Kroos M et al. Hum Mutat, 2008 Jun;29:E13-26; Bali DS et al. Muscle Nerve, 2011 May;43:665-70; Er TK et al. Clin Chim Acta, 2014 Feb;429:18-25; Johnson K et al. Orphanet J Rare Dis, 2017 Nov;12:173; Fukuhara Y et al. Mol Genet Metab Rep, 2018 Mar;14:3-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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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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Newborn screening for Pompe disease in Japan: report and literature review of mutations in the GAA gene in Japanese and Asian patients. | Momosaki K | Journal of human genetics | 2019 | PMID: 31076647 |
Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness. | Johnson K | Orphanet journal of rare diseases | 2017 | PMID: 29149851 |
A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan. | Fukuhara Y | Molecular genetics and metabolism reports | 2017 | PMID: 29124014 |
[Clinical characteristics and GAA gene mutation in children with glycogen storage disease type II: an analysis of 3 cases]. | Yuan S | Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics | 2017 | PMID: 29046207 |
Development of a feasible assay for the detection of GAA mutations in patients with Pompe disease. | Er TK | Clinica chimica acta; international journal of clinical chemistry | 2014 | PMID: 24444888 |
Remarkably low fibroblast acid α-glucosidase activity in three adults with Pompe disease. | Wens SC | Molecular genetics and metabolism | 2012 | PMID: 23000108 |
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 |
Molecular analysis and protein processing in late-onset Pompe disease patients with low levels of acid α-glucosidase activity. | Bali DS | Muscle & nerve | 2011 | PMID: 21484825 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c7d05e24-e761-491e-a660-67550a229253 | - | - | - | - |
Text-mined citations for rs528367092 ...
HelpRecord last updated Jun 17, 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.