ClinVar Genomic variation as it relates to human health
NM_006070.6(TFG):c.854C>T (p.Pro285Leu)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006070.6(TFG):c.854C>T (p.Pro285Leu)
Variation ID: 37089 Accession: VCV000037089.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q12.2 3: 100748182 (GRCh38) [ NCBI UCSC ] 3: 100467026 (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 Oct 14, 2014 Feb 28, 2024 Jun 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006070.6:c.854C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006061.2:p.Pro285Leu missense NM_001007565.2:c.854C>T NP_001007566.1:p.Pro285Leu missense NM_001195478.2:c.854C>T NP_001182407.1:p.Pro285Leu missense NM_001195479.2:c.842C>T NP_001182408.1:p.Pro281Leu missense NC_000003.12:g.100748182C>T NC_000003.11:g.100467026C>T NG_027821.2:g.43893C>T Q92734:p.Pro285Leu - Protein change
- P285L, P281L
- Other names
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- Canonical SPDI
- NC_000003.12:100748181:C:T
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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TFG | - | - |
GRCh38 GRCh37 |
411 | 426 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000030736.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 29, 2016 | RCV000218755.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 8, 2023 | RCV000642397.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2020 | RCV001095428.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 5, 2019 | RCV002251934.2 |
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
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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
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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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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary motor and sensory neuropathy, Okinawa type
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001136563.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely pathogenic
(Apr 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523397.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS3, PM2, PP1
Clinical Features:
Tremor (present) , Tetraparesis (present) , Muscular atrophy (present) , Myotonia (present) , Muscle spasm (present) , Fasciculations (present) , EMG: chronic denervation signs (present)
Geographic origin: Brazil
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Pathogenic
(Jun 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary motor and sensory neuropathy, Okinawa type
Hereditary spastic paraplegia 57
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: SCV000764067.6
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TFG function (PMID: 22883144, 24613659, 28196470). … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TFG function (PMID: 22883144, 24613659, 28196470). 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 not expected to disrupt TFG protein function. ClinVar contains an entry for this variant (Variation ID: 37089). This missense change has been observed in individuals with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) (PMID: 22883144, 23553329, 25725944). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs207482230, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the TFG protein (p.Pro285Leu). (less)
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Pathogenic
(Aug 18, 2015)
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criteria provided, single submitter
Method: research
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Hereditary motor and sensory neuropathy, Okinawa type
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000292367.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
This variant has been previously reported as disease-causing and was found in an individual with peripheral neuropathy.
Number of individuals with the variant: 1
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Pathogenic
(Feb 29, 2016)
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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: SCV000279619.9
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The P285L missense variant in the TFG gene has been previously reported to segregate with proximal hereditary motor and sensory neuropathy (HMSN-P) in several large … (more)
The P285L missense variant in the TFG gene has been previously reported to segregate with proximal hereditary motor and sensory neuropathy (HMSN-P) in several large families (Lee et al., 2013, Ishiura et al., 2012, Alavi et al., 2015). Functional studies demonstrate the P285L disrupts the protein and leads to inclusion body formation in cultured cells (Ishiura et al., 2012). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P285L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. (less)
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Likely pathogenic
(Mar 31, 2020)
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criteria provided, single submitter
Method: research
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Amyotrophic Lateral Sclerosis with Sensory Neuropathy
Affected status: yes
Allele origin:
germline
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Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University
Accession: SCV001251006.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Number of individuals with the variant: 4
Geographic origin: Anatolian Peninsula
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Pathogenic
(May 01, 2013)
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no assertion criteria provided
Method: literature only
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HEREDITARY MOTOR AND SENSORY NEUROPATHY, OKINAWA TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000053397.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 19, 2021 |
Comment on evidence:
In affected members of 4 Japanese families with Okinawa hereditary motor and sensory neuropathy (HMSNO; 604484), Ishiura et al. (2012) identified a heterozygous 854C-T transition … (more)
In affected members of 4 Japanese families with Okinawa hereditary motor and sensory neuropathy (HMSNO; 604484), Ishiura et al. (2012) identified a heterozygous 854C-T transition in the TFG gene, resulting in a pro285-to-leu (P285L) substitution at a highly conserved residue in the P/Q-rich domain in the C-terminal region. The mutation was not observed in 964 Japanese control chromosomes or in several exome databases. Two of the families were from the Kansai region and 2 were from Okinawa, and haplotype analysis suggested 2 independent origins of the mutation. The disorder was characterized clinically by young adult onset of proximal muscle weakness and atrophy, muscle cramps, and fasciculations, with later onset of distal sensory impairment. Neuropathologic examination of 1 patient showed TFG-immunopositive inclusion bodies in the motor neurons of the facial, hypoglossal, and abducens nuclei, and the spinal cord, as well as in the sensory neurons of the dorsal root ganglia. Inclusions were not found in glial cells. The TFG-immunopositive inclusions colocalized with ubiquitin deposition. In addition, phosphorylated TDP43 (605078)-positive inclusions were identified in motor and sensory neurons in the spinal cord; some inclusions were positive for both TFG and TDP43. There was also fragmentation of the Golgi apparatus in HMSNO motor neurons. Expression of the mutant TFG protein resulted in mislocalization and TDP43-inclusion-body formation in cultured cells. These findings suggested a pathogenic link to amyotrophic lateral sclerosis (ALS; 105400), in which TDP43 inclusions are found, and suggested that alteration of vesicle trafficking or RNA-mediated mechanisms might be involved in motor neuron degeneration in HMSNO. Lee et al. (2013) identified a heterozygous P285L mutation in the TFG gene in affected members of a Korean family with HMSNO. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases. TFG levels in patient peripheral nerves were similar to those in controls. The phenotype was characterized by young adult onset of proximal muscle weakness with cramping and fasciculations, and distal sensory impairment. Some of the patients had hand tremor early in the disease course, and MRI showed fatty replacement in proximal muscles of the lower limbs. (less)
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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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Proteasome impairment in neural cells derived from HMSN-P patient iPSCs. | Murakami N | Molecular brain | 2017 | PMID: 28196470 |
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. | Gonzaga-Jauregui C | Cell reports | 2015 | PMID: 26257172 |
Evidence of TRK-Fused Gene (TFG1) function in the ubiquitin-proteasome system. | Yagi T | Neurobiology of disease | 2014 | PMID: 24613659 |
Proximal dominant hereditary motor and sensory neuropathy with proximal dominance association with mutation in the TRK-fused gene. | Lee SS | JAMA neurology | 2013 | PMID: 23553329 |
The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement. | Ishiura H | American journal of human genetics | 2012 | PMID: 22883144 |
Text-mined citations for rs207482230 ...
HelpRecord last updated Mar 05, 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.