ClinVar Genomic variation as it relates to human health
NM_005609.4(PYGM):c.1768+1G>A
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_005609.4(PYGM):c.1768+1G>A
Variation ID: 194389 Accession: VCV000194389.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64751923 (GRCh38) [ NCBI UCSC ] 11: 64519395 (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 May 10, 2014 Feb 14, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005609.4:c.1768+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001164716.1:c.1504+1G>A splice donor NC_000011.10:g.64751923C>T NC_000011.9:g.64519395C>T NG_013018.1:g.13793G>A - Protein change
- Other names
- IVS14, G-A, +1
- Canonical SPDI
- NC_000011.10:64751922: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00007
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
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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
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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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PYGM | - | - |
GRCh38 GRCh37 |
1320 | 1334 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2023 | RCV000423322.7 | |
Pathogenic (1) |
criteria provided, single submitter
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May 19, 2015 | RCV000624349.2 | |
Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2024 | RCV000763265.17 |
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
(Dec 03, 2014)
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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: SCV000226114.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Glycogen storage disease, type V
Affected status: yes
Allele origin:
inherited
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002053924.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(May 19, 2015)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740890.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Rhabdomyolysis (present) , Elevated plasma acylcarnitine levels (present) , Anxiety (present) , Palpitations (present) , Premature birth (present) , Obesity (present)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type V
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003921114.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
A Heterozygous Splice site donor variant c.1768+1G>A in Exon 14 of the PYGM gene that results in the amino acid substitution was identified. The observed … (more)
A Heterozygous Splice site donor variant c.1768+1G>A in Exon 14 of the PYGM gene that results in the amino acid substitution was identified. The observed variant has allele frequency of 0.00002/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (ClinVar ID: 194389). This sequence change affects a donor splice site in intron 14 of the PYGM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (Baralle D et al., 2005). Disruption of this splice site has been observed in individuals with glycogen storage disease type V (GSD V), also known as McArdle disease (Lucia A et al., 2012 and Lorenzoni PJ et al., 2020). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Aug 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type V
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004207237.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type V
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019579.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type V
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893904.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jun 29, 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: SCV000521109.5
First in ClinVar: Mar 08, 2017 Last updated: Jul 08, 2023 |
Comment:
Previously published in association with McArdle disease (Tsujino et al., 1994; Rubio et al., 2007).; Canonical splice site variant in a gene for which loss-of-function … (more)
Previously published in association with McArdle disease (Tsujino et al., 1994; Rubio et al., 2007).; Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that the variant resulted in a truncated fragment that harbored a 67 base pair deletion (Tsujino et al., 1994); This variant is associated with the following publications: (PMID: 25914343, 26913921, 17221871, 34534370, 30415384, 31589614, 34276053, 8279469) (less)
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Pathogenic
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type V
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001392316.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 14 of the PYGM gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 14 of the PYGM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs771427957, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with glycogen storage disease type V (GSD V), also known as McArdle disease (PMID: 8279469, 22250184, 30415384). ClinVar contains an entry for this variant (Variation ID: 194389). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 1999)
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no assertion criteria provided
Method: literature only
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MCARDLE DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022553.2
First in ClinVar: Apr 04, 2013 Last updated: May 10, 2014 |
Comment on evidence:
Iyengar et al. (1997) restudied the consanguineous Druze family with McArdle disease (GSD5; 232600) reported by Sarova-Pinhas and Sadeh (1989) and found all affected subjects … (more)
Iyengar et al. (1997) restudied the consanguineous Druze family with McArdle disease (GSD5; 232600) reported by Sarova-Pinhas and Sadeh (1989) and found all affected subjects to be homozygous for a G-to-A transition in the first nucleotide of intron 14 of the PYGM gene, a mutation previously reported by Tsujino et al. (1994). This mutation resulted in activation of an upstream cryptic splice site in exon 14, causing deletion of 67 basepairs from exon 14 and affecting the glucose binding domain of PYGM. In a large Finnish kindred, Bruno et al. (1999) described the same mutation. The mutation at the 5-prime splice site of intron 14 was designated as 1844+G-A. (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 V
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001461275.1
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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Single-centre experience on genotypic and phenotypic features of southern Brazilian patients with McArdle disease. | Lorenzoni PJ | Acta neurologica Belgica | 2020 | PMID: 30415384 |
Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry. | Lucia A | Journal of neurology, neurosurgery, and psychiatry | 2012 | PMID: 22250184 |
McArdle disease: the mutation spectrum of PYGM in a large Italian cohort. | Bruno C | Human mutation | 2006 | PMID: 16786513 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Molecular characterization of McArdle's disease in two large Finnish families. | Bruno C | Journal of the neurological sciences | 1999 | PMID: 10450796 |
Homozygosity by descent for a rare mutation in the myophosphorylase gene is associated with variable phenotypes in a Druze family with McArdle disease. | Iyengar S | Journal of medical genetics | 1997 | PMID: 9152836 |
Three new mutations in patients with myophosphorylase deficiency (McArdle disease). | Tsujino S | American journal of human genetics | 1994 | PMID: 8279469 |
Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease). | Tsujino S | The New England journal of medicine | 1993 | PMID: 8316268 |
McArdle disease in a Druze family. | Sarova-Pinhas I | Israel journal of medical sciences | 1989 | PMID: 2703328 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PYGM | - | - | - | - |
Text-mined citations for rs771427957 ...
HelpRecord last updated Mar 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.