ClinVar contains an entry for this variant (Variation ID: 2313). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant has been observed in individual(s) with McArdle disease (PMID: 12929201, 23653251). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change affects codon 609 of the PYGM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PYGM protein. This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is present in population databases (rs119103259, gnomAD 0.003%).
ClinVar Genomic variation as it relates to human health
NM_005609.4(PYGM):c.1827G>A (p.Lys609=)
Germline
Classification
Help
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.
(8)
Help
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/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005609.4(PYGM):c.1827G>A (p.Lys609=)
Variation ID: 2313 Accession: VCV000002313.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.1 11: 64751597 (GRCh38) [ NCBI UCSC ] 11: 64519069 (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 Mar 24, 2015 Jun 17, 2024 Feb 29, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005609.4:c.1827G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005600.1:p.Lys609= synonymous NM_001164716.1:c.1563G>A NP_001158188.1:p.Lys521= synonymous NC_000011.10:g.64751597C>T NC_000011.9:g.64519069C>T NG_013018.1:g.14119G>A - Protein change
- -
- Other names
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K608K
- Canonical SPDI
- NC_000011.10:64751596:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| PYGM | - | - |
GRCh38 GRCh37 |
1343 | 1359 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 29, 2024 | RCV000002403.18 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Jun 24, 2020 | RCV002251858.2 |
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
(Sep 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486987.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jan 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002786688.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Aug 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001202452.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 2313). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
ClinVar contains an entry for this variant (Variation ID: 2313). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant has been observed in individual(s) with McArdle disease (PMID: 12929201, 23653251). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change affects codon 609 of the PYGM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PYGM protein. This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is present in population databases (rs119103259, gnomAD 0.003%). (less)
|
|
|
Pathogenic
(Jun 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523721.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM3, PP4
Clinical Features:
Rhabdomyolysis (present) , Myopathy (present) , Exercise intolerance (present) , Elevated circulating creatine kinase concentration (present)
Geographic origin: Brazil
|
|
|
Pathogenic
(Feb 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004207253.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Nov 25, 2003)
|
no assertion criteria provided
Method: literature only
|
MCARDLE DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022561.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2015 |
Comment on evidence:
In a patient with McArdle disease (GSD5; 232600), Fernandez-Cadenas et al. (2003) identified compound heterozygosity for mutations in the PYGM gene. One of the mutations, … (more)
In a patient with McArdle disease (GSD5; 232600), Fernandez-Cadenas et al. (2003) identified compound heterozygosity for mutations in the PYGM gene. One of the mutations, 1827G-A, was a silent mutation (lys608 to lys; K608K). cDNA studies showed that the change resulted in a severe mosaic alteration in mRNA splicing with multiple aberrant transcripts, including exon skipping, activation of cryptic splice sites, and exon-intron reorganization. The same mutation was identified in a second patient, supporting the idea that the K608K mutation has a primary pathogenic role. The second mutation was a 1722T-G transversion, resulting in a tyr573-to-ter (Y573X) (608455.0017) substitution. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Glycogen storage disease V
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001461274.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Glycogen storage disease, type V
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000172199.3
First in ClinVar: Jul 10, 2014 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM3, PP4
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:
ClinVar contains an entry for this variant (Variation ID: 2313). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant has been observed in individual(s) with McArdle disease (PMID: 12929201, 23653251). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change affects codon 609 of the PYGM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PYGM protein. This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is present in population databases (rs119103259, gnomAD 0.003%).
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM3, PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Glycogen Storage Disease Type V. | Adam MP | - | 2019 | PMID: 20301518 |
| Clinical and molecular characterization of McArdle's disease in Brazilian patients. | Gurgel-Giannetti J | Neuromolecular medicine | 2013 | PMID: 23653251 |
| Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry. | Lucia A | Journal of neurology, neurosurgery, and psychiatry | 2012 | PMID: 22250184 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Molecular characterization of myophosphorylase deficiency (McArdle disease) in 34 patients from Southern France: identification of 10 new mutations. Absence of genotype-phenotype correlation. | Aquaron R | Neuromuscular disorders : NMD | 2007 | PMID: 17324573 |
| Splicing mosaic of the myophosphorylase gene due to a silent mutation in McArdle disease. | Fernandez-Cadenas I | Neurology | 2003 | PMID: 14638972 |
| Two novel mutations in the muscle glycogen phosphorylase gene in McArdle's disease. | Gámez J | Muscle & nerve | 2003 | PMID: 12929201 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs119103259 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.