This sequence change falls in intron 2 of the GYG1 gene. It does not directly change the encoded amino acid sequence of the GYG1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs370652040, gnomAD 0.04%). This variant has been observed in individuals with polyglucosan body myopathy (PMID: 25272951, 26652229, 29264399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162661). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2 and introduces a premature termination codon (PMID: 25272951). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_004130.4(GYG1):c.143+3G>C
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004130.4(GYG1):c.143+3G>C
Variation ID: 162661 Accession: VCV000162661.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q24 3: 148994280 (GRCh38) [ NCBI UCSC ] 3: 148712067 (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 Feb 19, 2017 Oct 20, 2024 Feb 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004130.4:c.143+3G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001184720.2:c.143+3G>C intron variant NM_001184721.2:c.143+3G>C intron variant NC_000003.12:g.148994280G>C NC_000003.11:g.148712067G>C NG_027677.1:g.7873G>C - Protein change
- -
- Other names
-
IVS2DS, G-C, +3
- Canonical SPDI
- NC_000003.12:148994279:G:C
-
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.
-
0.00020 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00018
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
- 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. |
|||
| GYG1 | - | - |
GRCh38 GRCh37 |
271 | 308 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2024 | RCV000387284.22 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 10, 2024 | RCV001054146.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 17, 2019 | RCV001090151.3 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
May 2, 2023 | RCV000150098.7 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024931.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Sep 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease XV
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Undiagnosed Diseases Network, NIH
Accession: SCV001245599.1
First in ClinVar: May 12, 2020 Last updated: May 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Skeletal muscle atrophy (present) , Rheumatoid factor positive (present) , Proximal amyotrophy (present) , Myofibrillar myopathy (present) , Muscle weakness (present) , High palate (present) … (more)
Skeletal muscle atrophy (present) , Rheumatoid factor positive (present) , Proximal amyotrophy (present) , Myofibrillar myopathy (present) , Muscle weakness (present) , High palate (present) , Functional motor deficit (present) , Elevated serum creatine phosphokinase (present) , EMG: myopathic abnormalities (present) , Abnormality of muscle fibers (present) (less)
Age: 60-69 years
Sex: female
Ethnicity/Population group: Causasians
Tissue: blood
|
|
|
Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Polyglucosan body myopathy type 2
Glycogen storage disease XV
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001218447.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 2 of the GYG1 gene. It does not directly change the encoded amino acid sequence of the GYG1 protein. … (more)
This sequence change falls in intron 2 of the GYG1 gene. It does not directly change the encoded amino acid sequence of the GYG1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs370652040, gnomAD 0.04%). This variant has been observed in individuals with polyglucosan body myopathy (PMID: 25272951, 26652229, 29264399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162661). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2 and introduces a premature termination codon (PMID: 25272951). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329983.6
First in ClinVar: Dec 06, 2016 Last updated: Sep 29, 2024 |
Comment:
Published functional studies demonstrate that c.143+3 G>C results in abnormal splicing, leading to skipping of exon 2 (PMID: 25272951); This variant is associated with the … (more)
Published functional studies demonstrate that c.143+3 G>C results in abnormal splicing, leading to skipping of exon 2 (PMID: 25272951); This variant is associated with the following publications: (PMID: 27663060, 25272951, 27066558, 26652229, 26203156, 28256728, 29264399, 34426522, 31589614, 32905144) (less)
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002586000.15
First in ClinVar: Oct 22, 2022 Last updated: Oct 20, 2024 |
Comment:
GYG1: PP1:Strong, PM2, PM3, PS3:Moderate
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(May 02, 2023)
|
criteria provided, single submitter
Method: curation
|
Polyglucosan body myopathy type 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003922104.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
The heterozygous c.143+3G>C variant in GYG1 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 162665), in … (more)
The heterozygous c.143+3G>C variant in GYG1 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 162665), in one individual with polyglucosan body myopathy. This individual also carried a pathogenic variant (ClinVar Variation ID: 162665), however the phase of these variants are unknown at this time. The c.143+3G>C variant has been previously reported in 16 unrelated individuals with polyglucosan body myopathy 2 (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156) and segregated with disease in 3 affected relatives in one family (PMID: 29264399), but has been identified in 0.04% (50/128982) of European (non-Finnish) chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370652040). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 16 previously reported unrelated individuals, 11 were homozygotes (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156), and one was a reported compound heterozygote who carried a pathogenic variant in unknown phase (PMID: 29264399), and the patient identified by our study was also a reported compound heterozygote who carried a pathogenic variant in unknown phase (ClinVar Variation ID: 162665), which increases the likelihood that the c.143+3G>C variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 162661) and has been interpreted as pathogenic by the NIH Undiagnosed Disease Network, Invitae, CeGaT Center for Human Genetics Tuebingen, GeneDx, OMIM, and PerkinElmer Genomics. RT-PCR analysis of RNA from patient skeletal muscle tissue shows skipping of exon 2 and frameshift beginning at position 3 and leading to a premature termination codon 4 amino acids downstream (PMID: 25272951). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive polyglucosan body myopathy 2. ACMG/AMP Criteria applied: PS3_Moderate, PM3_Strong, PP1 (Richards 2015). (less)
|
|
|
Pathogenic
(Dec 01, 2014)
|
no assertion criteria provided
Method: literature only
|
POLYGLUCOSAN BODY MYOPATHY 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000196922.2
First in ClinVar: Jan 30, 2015 Last updated: Feb 19, 2017 |
Comment on evidence:
In 2 unrelated patients with onset of polyglucosan body myopathy-2 (PGBM2; 616199) in the first 2 decades of life, Malfatti et al. (2014) identified a … (more)
In 2 unrelated patients with onset of polyglucosan body myopathy-2 (PGBM2; 616199) in the first 2 decades of life, Malfatti et al. (2014) identified a homozygous G-to-C transversion (c.143+3G-C) in intron 2 of the GYG1 gene, resulting in aberrant splicing with the skipping of exon 2, a frameshift, and premature termination (Asp3GlufsTer4). Two additional unrelated patients with later onset of the disorder were found to be compound heterozygous for this splice site mutation and another pathogenic GYG1 mutation (see, e.g., R324X, 603942.0004). (less)
|
Comment:
Comment:
Published functional studies demonstrate that c.143+3 G>C results in abnormal splicing, leading to skipping of exon 2 (PMID: 25272951); This variant is associated with the following publications: (PMID: 27663060, 25272951, 27066558, 26652229, 26203156, 28256728, 29264399, 34426522, 31589614, 32905144)
Comment:
GYG1: PP1:Strong, PM2, PM3, PS3:Moderate
Comment:
The heterozygous c.143+3G>C variant in GYG1 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 162665), in one individual with polyglucosan body myopathy. This individual also carried a pathogenic variant (ClinVar Variation ID: 162665), however the phase of these variants are unknown at this time. The c.143+3G>C variant has been previously reported in 16 unrelated individuals with polyglucosan body myopathy 2 (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156) and segregated with disease in 3 affected relatives in one family (PMID: 29264399), but has been identified in 0.04% (50/128982) of European (non-Finnish) chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370652040). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 16 previously reported unrelated individuals, 11 were homozygotes (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156), and one was a reported compound heterozygote who carried a pathogenic variant in unknown phase (PMID: 29264399), and the patient identified by our study was also a reported compound heterozygote who carried a pathogenic variant in unknown phase (ClinVar Variation ID: 162665), which increases the likelihood that the c.143+3G>C variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 162661) and has been interpreted as pathogenic by the NIH Undiagnosed Disease Network, Invitae, CeGaT Center for Human Genetics Tuebingen, GeneDx, OMIM, and PerkinElmer Genomics. RT-PCR analysis of RNA from patient skeletal muscle tissue shows skipping of exon 2 and frameshift beginning at position 3 and leading to a premature termination codon 4 amino acids downstream (PMID: 25272951). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive polyglucosan body myopathy 2. ACMG/AMP Criteria applied: PS3_Moderate, PM3_Strong, PP1 (Richards 2015).
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:
This sequence change falls in intron 2 of the GYG1 gene. It does not directly change the encoded amino acid sequence of the GYG1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs370652040, gnomAD 0.04%). This variant has been observed in individuals with polyglucosan body myopathy (PMID: 25272951, 26652229, 29264399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162661). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2 and introduces a premature termination codon (PMID: 25272951). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
Published functional studies demonstrate that c.143+3 G>C results in abnormal splicing, leading to skipping of exon 2 (PMID: 25272951); This variant is associated with the following publications: (PMID: 27663060, 25272951, 27066558, 26652229, 26203156, 28256728, 29264399, 34426522, 31589614, 32905144)
Comment:
GYG1: PP1:Strong, PM2, PM3, PS3:Moderate
Comment:
The heterozygous c.143+3G>C variant in GYG1 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 162665), in one individual with polyglucosan body myopathy. This individual also carried a pathogenic variant (ClinVar Variation ID: 162665), however the phase of these variants are unknown at this time. The c.143+3G>C variant has been previously reported in 16 unrelated individuals with polyglucosan body myopathy 2 (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156) and segregated with disease in 3 affected relatives in one family (PMID: 29264399), but has been identified in 0.04% (50/128982) of European (non-Finnish) chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370652040). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 16 previously reported unrelated individuals, 11 were homozygotes (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156), and one was a reported compound heterozygote who carried a pathogenic variant in unknown phase (PMID: 29264399), and the patient identified by our study was also a reported compound heterozygote who carried a pathogenic variant in unknown phase (ClinVar Variation ID: 162665), which increases the likelihood that the c.143+3G>C variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 162661) and has been interpreted as pathogenic by the NIH Undiagnosed Disease Network, Invitae, CeGaT Center for Human Genetics Tuebingen, GeneDx, OMIM, and PerkinElmer Genomics. RT-PCR analysis of RNA from patient skeletal muscle tissue shows skipping of exon 2 and frameshift beginning at position 3 and leading to a premature termination codon 4 amino acids downstream (PMID: 25272951). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive polyglucosan body myopathy 2. ACMG/AMP Criteria applied: PS3_Moderate, PM3_Strong, PP1 (Richards 2015).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical heterogeneity and phenotype/genotype findings in 5 families with GYG1 deficiency. | Ben Yaou R | Neurology. Genetics | 2017 | PMID: 29264399 |
| Late-onset polyglucosan body myopathy in five patients with a homozygous mutation in GYG1. | Akman HO | Neuromuscular disorders : NMD | 2016 | PMID: 26652229 |
| A new muscle glycogen storage disease associated with glycogenin-1 deficiency. | Malfatti E | Annals of neurology | 2014 | PMID: 25272951 |
| 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 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs370652040 ...
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 Oct 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.