ClinVar Genomic variation as it relates to human health
NM_017739.4(POMGNT1):c.385C>T (p.Arg129Trp)
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.
Pathogenic(4); Likely pathogenic(4); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017739.4(POMGNT1):c.385C>T (p.Arg129Trp)
Variation ID: 558512 Accession: VCV000558512.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 46196047 (GRCh38) [ NCBI UCSC ] 1: 46661719 (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 Aug 5, 2018 Aug 4, 2024 Mar 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017739.4:c.385C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060209.4:p.Arg129Trp missense NM_001243766.2:c.385C>T NP_001230695.2:p.Arg129Trp missense NM_001290129.2:c.319C>T NP_001277058.2:p.Arg107Trp missense NM_001290130.2:c.-45C>T 5 prime UTR NC_000001.11:g.46196047G>A NC_000001.10:g.46661719G>A NG_009205.3:g.29259C>T LRG_701:g.29259C>T LRG_701t1:c.385C>T LRG_701p1:p.Arg129Trp LRG_701t2:c.385C>T LRG_701p2:p.Arg129Trp - Protein change
- R129W, R107W
- Other names
- NM_017739.4(POMGNT1):c.385C>T
- p.Arg129Trp
- Canonical SPDI
- NC_000001.11:46196046:G:A
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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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. |
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POMGNT1 | - | - |
GRCh38 GRCh37 |
260 | 1423 | |
TSPAN1 | - | - |
GRCh38 GRCh37 |
15 | 1154 |
Conditions - Germline
Condition
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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. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Apr 10, 2020 | RCV000674794.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV001099667.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV001099668.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2023 | RCV001200334.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV001244825.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2021 | RCV001788317.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 18, 2024 | RCV001810481.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002531361.9 |
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
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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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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2O
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001256140.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Congenital Muscular Dystrophy, alpha-dystroglycan related
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001256139.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Likely pathogenic
(Apr 10, 2020)
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criteria provided, single submitter
Method: research
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics
Accession: SCV001443801.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
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Likely pathogenic
(Nov 08, 2021)
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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 A3
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060204.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_017739.3(POMGNT1):c.385C>T(R129W) is a missense variant classified as likely pathogenic in the context of POMGNT-related disorders. R129W has been observed in cases with relevant disease (PMID: … (more)
NM_017739.3(POMGNT1):c.385C>T(R129W) is a missense variant classified as likely pathogenic in the context of POMGNT-related disorders. R129W has been observed in cases with relevant disease (PMID: 28688748, 30961548, Kritioti_2019_(no PMID; abstract)). Functional assessments of this variant are not available in the literature. R129W has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_017739.3(POMGNT1):c.385C>T(R129W) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(May 25, 2022)
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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: SCV002757415.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Comment:
Residue is located within the carbohydrate-binding stem domain and has been shown to modulate O-mannosylation of the alpha-dystroglycan protein; disruptions of this position destabilize the … (more)
Residue is located within the carbohydrate-binding stem domain and has been shown to modulate O-mannosylation of the alpha-dystroglycan protein; disruptions of this position destabilize the POMGNT1 enzyme, leading to decreased catalytic activity (Kuwabara et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 34324503, 28688748, 27493216, 30961548) (less)
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Likely pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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Muscular dystrophy-dystroglycanopathy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761199.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg129Trp variant in POMGNT1 has been reported in at least five individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy (PMID: 28688748, PMID: 30961548, PMID: 34324503, ClinVar SCV002029242.2), … (more)
The p.Arg129Trp variant in POMGNT1 has been reported in at least five individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy (PMID: 28688748, PMID: 30961548, PMID: 34324503, ClinVar SCV002029242.2), and has been identified in 0.002% (2/113568) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375431575). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID #558512) and has been interpreted as pathogenic by Invitae and CeGaT Center for Human Genetics Tuebingen, as likely pathogenic by Molecular Genetics (Royal Melbourne Hospital), Cytogenetics and Genomics Lab (Cyprus Institute Of Neurology and Genetics), and Myriad Women's Health, Inc., and as of uncertain significance by Counsyl, Illumina, and Natera, Inc. Of the five affected individuals, two were compound heterozygotes who carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Arg129Trp variant is pathogenic (PMID: 30961548, PMID: 34324503; ClinvarID: 56582, 984973). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PM3_Strong, PM2_supporting, PP3 (Richards 2015). (less)
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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2O
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
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
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Invitae
Accession: SCV001418070.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 129 of the POMGNT1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 129 of the POMGNT1 protein (p.Arg129Trp). This variant is present in population databases (rs375431575, gnomAD 0.003%). This missense change has been observed in individual(s) with muscular dystrophy-dystroglycanopathy or congenital muscular dystrophy (PMID: 28688748, 30961548, 34324503; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558512). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POMGNT1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002029243.3
First in ClinVar: Dec 12, 2021 Last updated: Apr 15, 2024 |
Comment:
This sequence change in POMGNT1 is predicted to replace arginine with tryptophan at codon 129, p.(Arg129Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in POMGNT1 is predicted to replace arginine with tryptophan at codon 129, p.(Arg129Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is a critical carbohydrate binding residue in the interleukin-like EMT inducer (ILEI) domain (PMID: 27493216). There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in gnomAD v2.1 is 0.002% (2/113,568 alleles) in the European (non-Finnish) population, which is consistent with a recessive condition. This variant has been detected in at least four individuals with muscular dystrophy-dystroglycanopathy. Of those individuals, three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and two of those were confirmed in trans by parental testing (PMID: 28688748, 30961548, 34324503). Further, the variant has been reported to segregate with disease in a single family (PMID: 34324503). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PM1, PM2_Supporting, PP1, PP3. (less)
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Pathogenic
(Mar 18, 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 A3
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004205957.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jul 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371263.22
First in ClinVar: Jul 16, 2020 Last updated: Aug 04, 2024 |
Comment:
POMGNT1: PM3:Strong, PM1, PM2, PP3, PS3:Supporting
Number of individuals with the variant: 2
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Uncertain significance
(Jan 31, 2020)
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no assertion criteria provided
Method: clinical testing
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Muscle-eye-brain disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002090227.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Unravelling the genetic causes of multiple malformation syndromes: A whole exome sequencing study of the Cypriot population. | Kritioti E | PloS one | 2021 | PMID: 34324503 |
Compound heterozygous POMGNT1 mutations leading to muscular dystrophy-dystroglycanopathy type A3: a case report. | Borisovna KO | BMC pediatrics | 2019 | PMID: 30961548 |
Congenital muscular dystrophies in the UK population: Clinical and molecular spectrum of a large cohort diagnosed over a 12-year period. | Sframeli M | Neuromuscular disorders : NMD | 2017 | PMID: 28688748 |
Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of α-dystroglycan. | Kuwabara N | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 27493216 |
Text-mined citations for rs375431575 ...
HelpRecord last updated Aug 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.