The c.15_23dupGGCGGCGGC variant in the PABPN1 gene has been reported previously in multiple individuals with oculopharyngeal muscular dystrophy (OPMD), and accounts for up to 40% of pathogenic PABPN1 expansion alleles (Brais et al., 1998; Trollet et al., 2014). The c.15_23dupGGCGGCGGC causes an in-frame duplication of 3 Alanine repeats expanding the normal tract of 10 Alanines to a pathogenic repeat expansion of 13 Alanines, denoted p.A9_A11dup. Sufficient data from control individuals in the NHLBI Exome Sequencing Project and Exome Aggregation Consortium data sets were not available to assess the frequency of the c.15_23dupGGCGGCGGC variant in the general population. We interpret c.15_23dupGGCGGCGGC as a pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_004643.3(PABPN1):c.3GGC[10] (p.Ala9_Ala11dup)
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004643.3(PABPN1):c.3GGC[10] (p.Ala9_Ala11dup)
Variation ID: 279930 Accession: VCV000279930.37
- Type and length
-
Microsatellite, 9 bp
- Location
-
Cytogenetic: 14q11.2 14: 23321471-23321472 (GRCh38) [ NCBI UCSC ] 14: 23790680-23790681 (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 Dec 6, 2016 Oct 20, 2024 Feb 23, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004643.4:c.15_23dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
inframe insertion initiator codon variant NM_004643.4:c.3GGC[10] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004634.1:p.Ala11_Gly12insAlaAlaAla inframe insertion initiator codon variant NM_001199864.3:c.433-709GGC[10] intron variant NM_001360551.3:c.3GGC[10] NP_001347480.1:p.Ala11_Gly12insAlaAlaAla inframe insertion initiator codon variant NM_001387340.1:c.550-709GGC[10] intron variant NM_001387341.1:c.529-709GGC[10] intron variant NM_001387342.1:c.529-709GGC[10] intron variant NM_001387343.1:c.529-709GGC[10] intron variant NM_001387344.1:c.529-709GGC[10] intron variant NM_001387345.1:c.433-709GGC[10] intron variant NM_001387346.1:c.433-709GGC[10] intron variant NM_004643.3:c.15_23dup NC_000014.9:g.23321472GGC[10] NC_000014.8:g.23790681GGC[10] NG_008239.1:g.6285GGC[10] NG_128768.1:g.363GGC[10] - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000014.9:23321471:GGCGGCGGCGGCGGCGGCGGC:GGCGGCGGCGGCGGCGGCGGCGGCGGCGGC
-
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.
-
0.00220 (GGCGGCGGCGGCGGCGGCGGCGGC)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| BCL2L2-PABPN1 | - | - | - |
GRCh38 GRCh37 |
- | 103 |
| PABPN1 | - | - |
GRCh38 GRCh37 |
1 | 96 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 27, 2023 | RCV000360117.26 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 8, 2023 | RCV000851331.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 22, 2023 | RCV004017579.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 23, 2024 | RCV004021060.1 |
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
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
(Nov 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329585.4
First in ClinVar: Dec 06, 2016 Last updated: Sep 03, 2023 |
Comment:
The c.15_23dupGGCGGCGGC variant in the PABPN1 gene has been reported previously in multiple individuals with oculopharyngeal muscular dystrophy (OPMD), and accounts for up to 40% … (more)
The c.15_23dupGGCGGCGGC variant in the PABPN1 gene has been reported previously in multiple individuals with oculopharyngeal muscular dystrophy (OPMD), and accounts for up to 40% of pathogenic PABPN1 expansion alleles (Brais et al., 1998; Trollet et al., 2014). The c.15_23dupGGCGGCGGC causes an in-frame duplication of 3 Alanine repeats expanding the normal tract of 10 Alanines to a pathogenic repeat expansion of 13 Alanines, denoted p.A9_A11dup. Sufficient data from control individuals in the NHLBI Exome Sequencing Project and Exome Aggregation Consortium data sets were not available to assess the frequency of the c.15_23dupGGCGGCGGC variant in the general population. We interpret c.15_23dupGGCGGCGGC as a pathogenic variant. (less)
|
|
|
Likely pathogenic
(Mar 12, 2019)
|
criteria provided, single submitter
Method: research
|
Oculopharyngeal muscular dystrophy 1
Affected status: yes
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV000993629.2 First in ClinVar: Sep 26, 2019 Last updated: Sep 03, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Paresthesia (present)
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Oculopharyngeal muscular dystrophy 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139400.2
First in ClinVar: Jan 09, 2020 Last updated: Sep 03, 2023 |
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446864.2
First in ClinVar: Nov 28, 2020 Last updated: Sep 03, 2023 |
Clinical Features:
Muscular dystrophy (present)
Sex: male
|
|
|
Pathogenic
(Apr 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Oculopharyngeal muscular dystrophy 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002798669.2
First in ClinVar: Dec 31, 2022 Last updated: Sep 03, 2023 |
|
|
|
Pathogenic
(Aug 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Oculopharyngeal muscular dystrophy 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016465.4
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Oculopharyngeal muscular dystrophy 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV004847219.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Method: Exome sequencing
|
|
|
Pathogenic
(Feb 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004999642.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.15_23dupGGCGGCGGC (p.A9_A11dup) alteration, located in coding exon 1 of the PABPN1 gene, results from an in-frame duplication of 9 nucleotides at positions 15 to … (more)
The c.15_23dupGGCGGCGGC (p.A9_A11dup) alteration, located in coding exon 1 of the PABPN1 gene, results from an in-frame duplication of 9 nucleotides at positions 15 to 23. This results in the insertion of 3 alanine residues between codons 9 and 11. This is a GCN trinucleotide repeat expansion with 13 repeats; also known as GCN[13]. Based on data from gnomAD, this allele has an overall frequency of 0.003% (1/29646) total alleles studied. The highest observed frequency was 0.007% (1/14964) of European (non-Finnish) alleles. Most individuals with oculopharyngeal muscular dystrophy carry a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of the PABPN1 gene (Trollet, 2020) This amino acid position is well conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197008.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Dec 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001502182.24
First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
Comment:
Comment:
The c.15_23dupGGCGGCGGC (p.A9_A11dup) alteration, located in coding exon 1 of the PABPN1 gene, results from an in-frame duplication of 9 nucleotides at positions 15 to 23. This results in the insertion of 3 alanine residues between codons 9 and 11. This is a GCN trinucleotide repeat expansion with 13 repeats; also known as GCN[13]. Based on data from gnomAD, this allele has an overall frequency of 0.003% (1/29646) total alleles studied. The highest observed frequency was 0.007% (1/14964) of European (non-Finnish) alleles. Most individuals with oculopharyngeal muscular dystrophy carry a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of the PABPN1 gene (Trollet, 2020) This amino acid position is well conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic.
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:
The c.15_23dupGGCGGCGGC variant in the PABPN1 gene has been reported previously in multiple individuals with oculopharyngeal muscular dystrophy (OPMD), and accounts for up to 40% of pathogenic PABPN1 expansion alleles (Brais et al., 1998; Trollet et al., 2014). The c.15_23dupGGCGGCGGC causes an in-frame duplication of 3 Alanine repeats expanding the normal tract of 10 Alanines to a pathogenic repeat expansion of 13 Alanines, denoted p.A9_A11dup. Sufficient data from control individuals in the NHLBI Exome Sequencing Project and Exome Aggregation Consortium data sets were not available to assess the frequency of the c.15_23dupGGCGGCGGC variant in the general population. We interpret c.15_23dupGGCGGCGGC as a pathogenic variant.
Comment:
The c.15_23dupGGCGGCGGC (p.A9_A11dup) alteration, located in coding exon 1 of the PABPN1 gene, results from an in-frame duplication of 9 nucleotides at positions 15 to 23. This results in the insertion of 3 alanine residues between codons 9 and 11. This is a GCN trinucleotide repeat expansion with 13 repeats; also known as GCN[13]. Based on data from gnomAD, this allele has an overall frequency of 0.003% (1/29646) total alleles studied. The highest observed frequency was 0.007% (1/14964) of European (non-Finnish) alleles. Most individuals with oculopharyngeal muscular dystrophy carry a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of the PABPN1 gene (Trollet, 2020) This amino acid position is well conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Oculopharyngeal Muscular Dystrophy. | Adam MP | - | 2020 | PMID: 20301305 |
Text-mined citations for rs193922941 ...
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 Nov 25, 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.