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NM_198994.3(TGM6):c.1550T>G (p.Leu517Trp)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Sep 13, 2021)
Last evaluated:
Nov 16, 2020
Accession:
VCV000031085.6
Variation ID:
31085
Description:
single nucleotide variant
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NM_198994.3(TGM6):c.1550T>G (p.Leu517Trp)

Allele ID
40042
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
20p13
Genomic location
20: 2417445 (GRCh38) GRCh38 UCSC
20: 2398091 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
O95932:p.Leu517Trp
NC_000020.10:g.2398091T>G
NC_000020.11:g.2417445T>G
... more HGVS
Protein change
L517W
Other names
-
Canonical SPDI
NC_000020.11:2417444:T:G
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (G)

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00011
1000 Genomes Project 0.00020
Links
ClinGen: CA259991
UniProtKB: O95932#VAR_065361
OMIM: 613900.0001
dbSNP: rs387907097
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 3 criteria provided, single submitter May 28, 2019 RCV000024080.5
Likely benign 1 criteria provided, single submitter Nov 16, 2020 RCV001659727.1
Pathogenic 1 no assertion criteria provided - RCV000077795.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
TGM6 - - GRCh38
GRCh37
238 267

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Spinocerebellar ataxia 35
Allele origin: unknown
Mendelics
Accession: SCV001142170.1
Submitted: (Oct 22, 2019)
Evidence details
Likely benign
(Nov 16, 2020)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: unknown
Athena Diagnostics Inc
Accession: SCV001880913.1
Submitted: (Sep 13, 2021)
Evidence details
Publications
PubMed (10)
Pathogenic
(Dec 01, 2010)
no assertion criteria provided
Method: literature only
SPINOCEREBELLAR ATAXIA 35
Allele origin: germline
OMIM
Accession: SCV000045371.1
Submitted: (Apr 19, 2011)
Evidence details
Publications
PubMed (1)
pathogenic
(-)
no assertion criteria provided
Method: not provided
AML - Acute myeloid leukemia
Allele origin: germline, inherited
Fujian Institute of Hematology,Fujian Medical University
Accession: SCV000109629.1
Submitted: (Jan 09, 2014)
Comment:
The variant was predicted to be deleterious and may be associated with familial acute myeloid leukemia. A genome-wide linkage scan using a 500K SNP genotyping … (more)
Evidence details
Comment:
Converted during submission to Pathogenic.
Pathogenic
(Feb 28, 2019)
no assertion criteria provided
Method: provider interpretation
Spinocerebellar ataxia 35
Allele origin: germline
Codex Genetics Limited
Accession: SCV000996012.1
Submitted: (Jul 02, 2019)
Evidence details
Publications
PubMed (1)

Functional evidence

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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 this variant

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Title Author Journal Year Link
<i>TGM6</i> L517W is not a pathogenic variant for spinocerebellar ataxia type 35. Chen Y Neurology. Genetics 2020 PMID: 32426513
<i>TGM6</i> variants in Parkinson's disease: clinical findings and functional evidence. Chen K Journal of integrative neuroscience 2020 PMID: 32259886
A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases. Yu AC Frontiers in neuroscience 2019 PMID: 31920494
A significant inflation in TGM6 genetic risk casts doubt in its causation in spinocerebellar ataxia type 35. Fung JLF Parkinsonism & related disorders 2019 PMID: 30670339
Hispanic Spinocerebellar Ataxia Type 35 (SCA35) with a Novel Frameshift Mutation. Lin CC Cerebellum (London, England) 2019 PMID: 30229425
Mutations in TGM6 induce the unfolded protein response in SCA35. Tripathy D Human molecular genetics 2017 PMID: 28934387
Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia. Pan LL European journal of human genetics : EJHG 2015 PMID: 24755948
Spinocerebellar ataxia 35: novel mutations in TGM6 with clinical and genetic characterization. Guo YC Neurology 2014 PMID: 25253745
Spinocerebellar ataxia type 35 (SCA35)-associated transglutaminase 6 mutants sensitize cells to apoptosis. Guan WJ Biochemical and biophysical research communications 2013 PMID: 23206699
TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Wang JL Brain : a journal of neurology 2010 PMID: 21106500

Text-mined citations for rs387907097...

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These 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, 2021