Variant summary: POMT1 c.2106_2116del11 (p.Val703LeufsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory but have been reported in association with Walker-Warburg Syndrome and other POMT1 associated phenotypes in the HGMD/LOVD databases. The variant was absent in 232498 control chromosomes. c.2106_2116del11 has been reported in the literature as a homozygous genotype in at-least one individual affected with Walker-Warburg Syndrome (example, Beltran-Valero de Bernabe_2002) and has subsequently been cited by numerous authors without primary evidence (example, Balci_2005, Currier_2005, Akasaka-Manya_2006, can Reeuwijk_2006, Akasaka-Manya_2004). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001077365.2(POMT1):c.2040_2050del (p.Val681fs)
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.
(3)
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
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001077365.2(POMT1):c.2040_2050del (p.Val681fs)
Variation ID: 1343631 Accession: VCV001343631.7
- Type and length
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Deletion, 11 bp
- Location
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Cytogenetic: 9q34.13 9: 131522962-131522972 (GRCh38) [ NCBI UCSC ] 9: 134398349-134398359 (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 Mar 12, 2022 Jun 17, 2024 Jan 21, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001077365.2:c.2040_2050del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001070833.1:p.Val681fs frameshift NM_001077366.2:c.1878_1888del NP_001070834.1:p.Val627fs frameshift NM_001136113.2:c.2040_2050del NP_001129585.1:p.Val681fs frameshift NM_001136114.2:c.1689_1699del NP_001129586.1:p.Val564fs frameshift NM_001353193.2:c.2106_2116del NP_001340122.2:p.Val703fs frameshift NM_001353194.2:c.1878_1888del NP_001340123.1:p.Val627fs frameshift NM_001353195.2:c.1689_1699del NP_001340124.1:p.Val564fs frameshift NM_001353196.2:c.1950_1960del NP_001340125.1:p.Val651fs frameshift NM_001353197.2:c.1944_1954del NP_001340126.2:p.Val649fs frameshift NM_001353198.2:c.1944_1954del NP_001340127.2:p.Val649fs frameshift NM_001353199.2:c.1755_1765del NP_001340128.2:p.Val586fs frameshift NM_001353200.2:c.1584_1594del NP_001340129.1:p.Val529fs frameshift NM_001374689.1:c.2028_2038del NP_001361618.1:p.Val677fs frameshift NM_001374690.1:c.1821_1831del NP_001361619.1:p.Val608fs frameshift NM_001374691.1:c.1689_1699del NP_001361620.1:p.Val564fs frameshift NM_001374692.1:c.1689_1699del NP_001361621.1:p.Val564fs frameshift NM_001374693.1:c.1689_1699del NP_001361622.1:p.Val564fs frameshift NM_001374695.1:c.1650_1660del NP_001361624.1:p.Val551fs frameshift NM_007171.4:c.2106_2116del NP_009102.4:p.Val703fs frameshift NR_148391.2:n.2074_2084del non-coding transcript variant NR_148392.2:n.2292_2302del non-coding transcript variant NR_148393.2:n.2213_2223del non-coding transcript variant NR_148394.2:n.1967_1977del non-coding transcript variant NR_148395.2:n.2365_2375del non-coding transcript variant NR_148396.2:n.1999_2009del non-coding transcript variant NR_148397.2:n.2124_2134del non-coding transcript variant NR_148398.2:n.2079_2089del non-coding transcript variant NR_148399.2:n.2605_2615del non-coding transcript variant NR_148400.2:n.2204_2214del non-coding transcript variant NC_000009.12:g.131522968_131522978del NC_000009.11:g.134398355_134398365del NG_008896.2:g.25067_25077del LRG_842:g.25067_25077del LRG_842t1:c.2106_2116del LRG_842p1:p.Val703fs LRG_842t2:c.2040_2050del LRG_842p2:p.Val681fs - Protein change
- V529fs, V551fs, V564fs, V586fs, V608fs, V627fs, V649fs, V651fs, V677fs, V681fs, V703fs
- Other names
- -
- Canonical SPDI
- NC_000009.12:131522961:CCTGGTGGTGGCCTGGT:CCTGGT
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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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| POMT1 | - | - |
GRCh38 GRCh37 |
1160 | 1201 | |
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 (1) |
criteria provided, single submitter
|
Aug 8, 2023 | RCV002034732.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 18, 2022 | RCV001844648.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 21, 2024 | RCV003475106.2 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Feb 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103835.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: POMT1 c.2106_2116del11 (p.Val703LeufsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: POMT1 c.2106_2116del11 (p.Val703LeufsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory but have been reported in association with Walker-Warburg Syndrome and other POMT1 associated phenotypes in the HGMD/LOVD databases. The variant was absent in 232498 control chromosomes. c.2106_2116del11 has been reported in the literature as a homozygous genotype in at-least one individual affected with Walker-Warburg Syndrome (example, Beltran-Valero de Bernabe_2002) and has subsequently been cited by numerous authors without primary evidence (example, Balci_2005, Currier_2005, Akasaka-Manya_2006, can Reeuwijk_2006, Akasaka-Manya_2004). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
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Pathogenic
(Aug 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1
Walker-Warburg congenital muscular dystrophy Autosomal recessive limb-girdle muscular dystrophy type 2K
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: SCV002146747.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This variant disrupts a region of the POMT1 protein in which other variant(s) (p.Asp723Glyfs*8) have been determined to be pathogenic (PMID: 12369018, 16575835, 17559086, 22323514, … (more)
This variant disrupts a region of the POMT1 protein in which other variant(s) (p.Asp723Glyfs*8) have been determined to be pathogenic (PMID: 12369018, 16575835, 17559086, 22323514, 24304607, 24491487). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1343631). This variant has not been reported in the literature in individuals affected with POMT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val703Leufs*24) in the POMT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the POMT1 protein. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204047.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
Comment:
Comment:
This variant disrupts a region of the POMT1 protein in which other variant(s) (p.Asp723Glyfs*8) have been determined to be pathogenic (PMID: 12369018, 16575835, 17559086, 22323514, 24304607, 24491487). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1343631). This variant has not been reported in the literature in individuals affected with POMT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val703Leufs*24) in the POMT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the POMT1 protein. For these reasons, this variant has been 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:
Variant summary: POMT1 c.2106_2116del11 (p.Val703LeufsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory but have been reported in association with Walker-Warburg Syndrome and other POMT1 associated phenotypes in the HGMD/LOVD databases. The variant was absent in 232498 control chromosomes. c.2106_2116del11 has been reported in the literature as a homozygous genotype in at-least one individual affected with Walker-Warburg Syndrome (example, Beltran-Valero de Bernabe_2002) and has subsequently been cited by numerous authors without primary evidence (example, Balci_2005, Currier_2005, Akasaka-Manya_2006, can Reeuwijk_2006, Akasaka-Manya_2004). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
This variant disrupts a region of the POMT1 protein in which other variant(s) (p.Asp723Glyfs*8) have been determined to be pathogenic (PMID: 12369018, 16575835, 17559086, 22323514, 24304607, 24491487). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1343631). This variant has not been reported in the literature in individuals affected with POMT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val703Leufs*24) in the POMT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the POMT1 protein. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations. | Wallace SE | Neuromuscular disorders : NMD | 2014 | PMID: 24491487 |
| Detection limit of intragenic deletions with targeted array comparative genomic hybridization. | Askree SH | BMC genetics | 2013 | PMID: 24304607 |
| Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. | Devisme L | Brain : a journal of neurology | 2012 | PMID: 22323514 |
| Molecular heterogeneity in fetal forms of type II lissencephaly. | Bouchet C | Human mutation | 2007 | PMID: 17559086 |
| Physical and functional association of human protein O-mannosyltransferases 1 and 2. | Akasaka-Manya K | The Journal of biological chemistry | 2006 | PMID: 16698797 |
| The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation. | van Reeuwijk J | Human mutation | 2006 | PMID: 16575835 |
| An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. | Balci B | Neuromuscular disorders : NMD | 2005 | PMID: 15792865 |
| Glyc-O-genetics of Walker-Warburg syndrome. | van Reeuwijk J | Clinical genetics | 2005 | PMID: 15733261 |
| Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome. | Currier SC | American journal of medical genetics. Part A | 2005 | PMID: 15637732 |
| Mutations of the POMT1 gene found in patients with Walker-Warburg syndrome lead to a defect of protein O-mannosylation. | Akasaka-Manya K | Biochemical and biophysical research communications | 2004 | PMID: 15522202 |
| Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. | Beltrán-Valero de Bernabé D | American journal of human genetics | 2002 | PMID: 12369018 |
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Text-mined citations for rs1950265792 ...
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.