ClinVar Genomic variation as it relates to human health
NM_006070.6(TFG):c.317G>A (p.Arg106His)
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(2); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006070.6(TFG):c.317G>A (p.Arg106His)
Variation ID: 1075540 Accession: VCV001075540.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q12.2 3: 100728760 (GRCh38) [ NCBI UCSC ] 3: 100447604 (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 May 10, 2021 Feb 28, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006070.6:c.317G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006061.2:p.Arg106His missense NM_001007565.2:c.317G>A NP_001007566.1:p.Arg106His missense NM_001195478.2:c.317G>A NP_001182407.1:p.Arg106His missense NM_001195479.2:c.317G>A NP_001182408.1:p.Arg106His missense NM_006070.5:c.317G>A NM_006070.5:c.[317G>A] NC_000003.12:g.100728760G>A NC_000003.11:g.100447604G>A NG_027821.2:g.24471G>A - Protein change
- R106H
- Other names
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- Canonical SPDI
- NC_000003.12:100728759: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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
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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 |
409 | 424 |
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
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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 (1) |
criteria provided, single submitter
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Aug 24, 2023 | RCV001389156.7 | |
Likely pathogenic (2) |
criteria provided, single submitter
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- | RCV001542526.6 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2021 | RCV001780372.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 21, 2021 | RCV002322372.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 27, 2023 | RCV003479321.1 |
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
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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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Likely pathogenic
(Jul 19, 2021)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002064430.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
The p.Arg106His change affects a highly conserved amino acid residue located in a domain of the TFG protein that is not known to be functional. … (more)
The p.Arg106His change affects a highly conserved amino acid residue located in a domain of the TFG protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg106His substitution. This particular amino acid change was described in a homozygous state in a family with pure hereditary spastic paraplegias (HSP) (PMID: 27492651). Expression studies showed that the mutant protein showed mitochondrial fragmentation, observed in neurodegenerative diseases (PMID: 27492651). This sequence change has been described in the gnomAD database with a low population frequency of 0.036% in the South Asian subpopulation (dbSNP rs376971794). Other pathogenic sequence change affecting the same amino acid residue (p.Arg106) have been described in the literature (PMIDs: 23479643, 27492651, 29971521). (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 57
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073211.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The missense variant p.R106H in TFG (NM_006070.6) has been reported previously in homozygous state in affected individuals (Beetz C et al, Harlalka GV et al). … (more)
The missense variant p.R106H in TFG (NM_006070.6) has been reported previously in homozygous state in affected individuals (Beetz C et al, Harlalka GV et al). The variant has been submitted to ClinVar as Pathogenic. The p.R106H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 106 of TFG is conserved in all mammalian species. The nucleotide c.317 in TFG is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Frequent falls (present) , Difficulty walking (present) , Hypotonia (present) , Tip-toe gait (present) , Gowers sign (present) , Gait disturbance (present) , Generalized muscle … (more)
Frequent falls (present) , Difficulty walking (present) , Hypotonia (present) , Tip-toe gait (present) , Gowers sign (present) , Gait disturbance (present) , Generalized muscle hypertrophy (present) , Brisk reflexes (present) , EEG abnormality (present) , Spastic paraplegia (present) (less)
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Uncertain significance
(Jul 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002610201.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R106H variant (also known as c.317G>A), located in coding exon 3 of the TFG gene, results from a G to A substitution at nucleotide … (more)
The p.R106H variant (also known as c.317G>A), located in coding exon 3 of the TFG gene, results from a G to A substitution at nucleotide position 317. The arginine at codon 106 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in the homozygote state and segregates with spastic paraplegia 57 (SPG57) in one family, and experimental studies show that this alteration may alter TFG function and disrupt the p.R106 amino acid residue (Harlalka GV et al. Hum Mutat, 2016 11;37:1157-1161). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of hereditary motor and sensory neuropathy, Okinawa type (HMSN-P); however, its contribution to the development of spastic paraplegia 57 (SPG57) is uncertain. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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TFG-Related Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223189.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: TFG c.317G>A (p.Arg106His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: TFG c.317G>A (p.Arg106His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250224 control chromosomes. c.317G>A has been reported in the literature in multiple homozygous individuals affected with autosomal recessive hereditary spastic paraplegia, in one family with disease co-segregation (e.g. Harlalka_2016). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function demonstrating decreased mitochondrial continuity index (MCI), a measure of mitochondrial fragmentation and impaired mitochondrial function (e.g. Harlalka_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27492651, 33726816). A different variant located at the same codon (c.316C>T, p.Arg106Cys) has been classified as pathogenic with a severely presenting phenotype of TFG-Associated Hereditary Spastic Paraplegia, supporting a critical relevance of this residue to TFG protein function. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=1), likely pathogenic (n=2), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(May 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016876.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 24, 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: SCV001590422.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 106 of the TFG protein (p.Arg106His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 106 of the TFG protein (p.Arg106His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg106 amino acid residue in TFG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23479643, 27492651, 29971521). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TFG function (PMID: 27492651). 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 TFG protein function. ClinVar contains an entry for this variant (Variation ID: 1075540). This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 27492651). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs376971794, gnomAD 0.04%). (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hereditary spastic paraplegia 57
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760099.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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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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Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. | Stranneheim H | Genome medicine | 2021 | PMID: 33726816 |
R106C TFG variant causes infantile neuroaxonal dystrophy "plus" syndrome. | Catania A | Neurogenetics | 2018 | PMID: 29971521 |
Novel Genetic, Clinical, and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia. | Harlalka GV | Human mutation | 2016 | PMID: 27492651 |
Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure. | Beetz C | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23479643 |
Text-mined citations for rs376971794 ...
HelpRecord last updated Apr 06, 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.