ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.761C>T (p.Ser254Leu)
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.
Pathogenic(2); Likely pathogenic(3); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000152.5(GAA):c.761C>T (p.Ser254Leu)
Variation ID: 325782 Accession: VCV000325782.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80107625 (GRCh38) [ NCBI UCSC ] 17: 78081424 (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 Dec 6, 2016 Jan 6, 2024 Nov 22, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.761C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Ser254Leu missense NM_000152.4:c.761C>T NM_001079803.3:c.761C>T NP_001073271.1:p.Ser254Leu missense NM_001079804.3:c.761C>T NP_001073272.1:p.Ser254Leu missense NC_000017.11:g.80107625C>T NC_000017.10:g.78081424C>T NG_009822.1:g.11070C>T LRG_673:g.11070C>T LRG_673t1:c.761C>T P10253:p.Ser254Leu - Protein change
- S254L
- Other names
- -
- Canonical SPDI
- NC_000017.11:80107624:C:T
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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00021
Exome Aggregation Consortium (ExAC) 0.00022
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
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 |
2793 | 2844 |
Conditions - Germline
Condition
Help
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
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. |
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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Aug 28, 2022 | RCV000285433.17 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Nov 22, 2022 | RCV000498412.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 18, 2022 | RCV002265734.2 |
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. |
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Likely pathogenic
(Jun 14, 2016)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000407271.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Jan 24, 2018)
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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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Baylor Genetics
Accession: SCV001528212.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810440.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Uncertain significance
(Jun 18, 2021)
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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: SCV000590492.3
First in ClinVar: Aug 20, 2017 Last updated: Sep 24, 2021 |
Comment:
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: 29122469, … (more)
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: 29122469, 18458862, 25466677, 27183828, 24513544, 29451150, 29124014, 31637888, 31980526) (less)
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Likely pathogenic
(Jan 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: SCV002501222.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Uncertain significance
(Sep 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547857.2
First in ClinVar: Jul 18, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: GAA c.761C>T (p.Ser254Leu) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein … (more)
Variant summary: GAA c.761C>T (p.Ser254Leu) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282470 control chromosomes, predominantly at a frequency of 0.0028 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00019 vs 0.0042), allowing no conclusion about variant significance. c.761C>T has been reported in the literature as a complex allele in cis with c.752C>T (p.Ser251Leu) in settings of newborn screening for Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Labrousse_2010, Chien_2011, Liao_2014). This complex allele has been observed as a homozygous and compound heterozygous genotype in the ascertained reports among newborns with screening enzyme activity below the cutoff value (example, Liao_2014). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Glycogen Storage Disease, Type 2 (Pompe Disease). Co-occurrences of this complex allele in cis with other pathogenic variant(s) have been reported in the literature (GAA c.1411_1414del , p.E471PfsX5), providing supporting evidence for a benign role (example, Larousse_2010, Liao_2014). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=2; P/LP, n=6). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Pathogenic
(Aug 28, 2022)
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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: SCV000626639.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
The c.761C>T sequence change replaces serine with leucine at codon 254 of the GAA protein (p.Ser254Leu). The serine residue is highly conserved and there is … (more)
The c.761C>T sequence change replaces serine with leucine at codon 254 of the GAA protein (p.Ser254Leu). The serine residue is highly conserved and there is a large physiochemical difference between serine and leucine. This variant is present in population databases (rs577915581, gnomAD 0.3%). The c.761C>T (p.Ser254Leu) variant frequently co-occurs with the c.752C>T (p.Ser251Leu) variant (rs200856561) in cis (on the same chromosome), which is known as the c.[752C>T;761C>T] haplotype. This haplotype has been reported in the literature as homozygous or in combination with other GAA variants in multiple individuals affected with Pompe disease (PMID: 24513544, 29124014, 27183828). The clinical significance of the c.761C>T variant alone is unclear. ClinVar contains an entry for this variant (Variation ID: 325782). ClinVar contains an entry for this variant (Variation ID: 325782). While the c.761C>T (p.Ser254Leu) variant alone has not been shown to affect GAA protein function, the c.[752C>T;761C>T] haplotype has been reported to reduce enzyme activity (PMID: 22644586). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this haplotype has been classified as Pathogenic. (less)
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Pathogenic
(Nov 22, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224256.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 11, 2019)
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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:
unknown
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Counsyl
Accession: SCV001132197.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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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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The First Year Experience of Newborn Screening for Pompe Disease in California. | Tang H | International journal of neonatal screening | 2020 | PMID: 33073007 |
A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders. | Sanders KA | International journal of neonatal screening | 2020 | PMID: 32802993 |
Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: Evidence from real-world experiences. | Chien YH | Molecular genetics and metabolism reports | 2020 | PMID: 32373469 |
Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns. | Chien YH | Orphanet journal of rare diseases | 2020 | PMID: 32014045 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Implementation of a Targeted Next-Generation Sequencing Panel for Constitutional Newborn Screening in High-Risk Neonates. | Lee H | Yonsei medical journal | 2019 | PMID: 31637888 |
Newborn screening: Taiwanese experience. | Chien YH | Annals of translational medicine | 2019 | PMID: 31392193 |
Gene-specific features enhance interpretation of mutational impact on acid α-glucosidase enzyme activity. | Adhikari AN | Human mutation | 2019 | PMID: 31228295 |
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 Seven Novel Mutations in the Acid Alpha-glucosidase Gene in Five Chinese Patients with Late-onset Pompe Disease. | Liu HX | Chinese medical journal | 2018 | PMID: 29451150 |
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 |
Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease. | Mori M | Molecular genetics and metabolism | 2017 | PMID: 29122469 |
Mass Spectrometry but Not Fluorimetry Distinguishes Affected and Pseudodeficiency Patients in Newborn Screening for Pompe Disease. | Liao HC | Clinical chemistry | 2017 | PMID: 28450385 |
Liquid Chromatography-Tandem Mass Spectrometry Assay of Leukocyte Acid α-Glucosidase for Post-Newborn Screening Evaluation of Pompe Disease. | Lin N | Clinical chemistry | 2017 | PMID: 28196920 |
Slow, progressive myopathy in neonatally treated patients with infantile-onset Pompe disease: a muscle magnetic resonance imaging study. | Peng SS | Orphanet journal of rare diseases | 2016 | PMID: 27183828 |
Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. | Chien YH | The Journal of pediatrics | 2015 | PMID: 25466677 |
Detecting multiple lysosomal storage diseases by tandem mass spectrometry--a national newborn screening program in Taiwan. | Liao HC | Clinica chimica acta; international journal of clinical chemistry | 2014 | PMID: 24513544 |
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 |
Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. | Chien YH | The Journal of pediatrics | 2011 | PMID: 21232767 |
Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program. | Labrousse P | Molecular genetics and metabolism | 2010 | PMID: 20080426 |
Identification of eight novel mutations of the acid alpha-glucosidase gene causing the infantile or juvenile form of glycogen storage disease type II. | Wan L | Journal of neurology | 2008 | PMID: 18458862 |
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Text-mined citations for rs577915581 ...
HelpRecord last updated Mar 30, 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.