ClinVar Genomic variation as it relates to human health
NM_000359.3(TGM1):c.420A>G (p.Ile140Met)
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_000359.3(TGM1):c.420A>G (p.Ile140Met)
Variation ID: 372784 Accession: VCV000372784.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q12 14: 24261783 (GRCh38) [ NCBI UCSC ] 14: 24730989 (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 Jan 9, 2017 Feb 14, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000359.3:c.420A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000350.1:p.Ile140Met missense NC_000014.9:g.24261783T>C NC_000014.8:g.24730989T>C NG_007150.1:g.6384A>G - Protein change
- I140M
- Other names
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- Canonical SPDI
- NC_000014.9:24261782:T:C
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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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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00014
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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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TGM1 | - | - |
GRCh38 GRCh38 GRCh37 |
968 | 1001 |
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
Help
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000414724.4 | |
Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Oct 29, 2023 | RCV001275151.10 |
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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Likely pathogenic
(Jun 06, 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: SCV000491276.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment:
The I140M variant in the TGM1 gene has been reported previously in a two patients with collodion membrane who were also heterozygous for another TGM1 … (more)
The I140M variant in the TGM1 gene has been reported previously in a two patients with collodion membrane who were also heterozygous for another TGM1 variant on the opposite allele (Zhang et al., 2012; Chang et al., 2007). I140M was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. It is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties and occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Nevertheless, in silico analysis predicts this variant is probably damaging to the protein structure/function, and other missense variants in nearby residues (R142C/P/H, R143C/H, G144R/E) have been reported in the Human Gene Mutation Database in association with lamellar ichthyosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the I140M variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
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Likely pathogenic
(Jul 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556846.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
The TGM1 c.420A>G variant is classified as a LIKELY PATHOGENIC (PS3, PM2, PP4, PS4_Supporting) This variant is a single nucleotide change in exon 3/15 of … (more)
The TGM1 c.420A>G variant is classified as a LIKELY PATHOGENIC (PS3, PM2, PP4, PS4_Supporting) This variant is a single nucleotide change in exon 3/15 of the TGM1 gene, which is predicted to change the amino acid isoleucine at position 140 in the protein to methionine. This variant is located in protein domains of the TGM1 gene. Functional studies have demonstrated that this variant disrupts TGM1 protein function (PMID: 26990434) (PS3). This variant has been reported multiple times in individuals with congenital Ichthyosis who were also heterozygous for another TGM1 variant (PMID: 22311480, 25154629, 25766764). The variant has been reported in dbSNP (rs139208806) but is present at low frequency in population databases (gnomAD 12/152024, 0 homozygote) (PM2). The variant has been reported in ClinVar (Variation ID: 372784) and HGMD (Accession no.: CM123548) as likely pathogenic/pathogenic/disease causing (PS4_supporting). Computational predictions are conflicting. Patient's phenotype is highly specific for the TGM1 gene (PP4). (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 1
Affected status: unknown
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002764006.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(Feb 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002782342.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Oct 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 1
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920558.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
This variant has been reported in the literature in the compound heterozygous state in at least two individuals with congenital ichthyosis and was confirmed to … (more)
This variant has been reported in the literature in the compound heterozygous state in at least two individuals with congenital ichthyosis and was confirmed to be in trans (present on opposite alleles) with another disease-causing variant in one of these individuals (Zhang 2012 PMID: 22311480; Numata 2015 PMID: 25766764). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.1% [21/19948]; https://gnomad.broadinstitute.org/variant/14-24730989-T-C?dataset=gnomad_r2_1); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is also present in ClinVar, with multiple laboratories classifying it as pathogenic or likely pathogenic (Variation ID: 372784). Evolutionary conservation and computational prediction tools for this variant are unclear. In vitro functional studies have shown that this variant impairs expression of the encoded protein at the cell membrane (Numata 2016 PMID: 26990434); however, these studies may not accurately represent in vivo biological function. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. (less)
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Likely pathogenic
(Oct 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004203726.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016880.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 19, 2024)
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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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Invitae
Accession: SCV002147796.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 140 of the TGM1 protein (p.Ile140Met). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 140 of the TGM1 protein (p.Ile140Met). This variant is present in population databases (rs139208806, gnomAD 0.1%). This missense change has been observed in individual(s) with congenital ichthyosis (PMID: 22311480, 25154629, 25766764). 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: 372784). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TGM1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TGM1 function (PMID: 26990434). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive congenital ichthyosis type 1
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001459989.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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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Functional study of TGM1 missense mutations in autosomal recessive congenital ichthyosis. | Numata S | Experimental dermatology | 2016 | PMID: 26990434 |
Mutation study for 9 genes in 23 unrelated patients with autosomal recessive congenital ichthyosis in Japan and Malaysia. | Numata S | Journal of dermatological science | 2015 | PMID: 25766764 |
Mutations of transglutaminase-1 in Chinese patients with autosomal recessive congenital ichthyosis: a case report with clinical and genetic analysis of Chinese cases reported in literature. | Liu JJ | Clinical and experimental dermatology | 2015 | PMID: 25154629 |
[Novel compound heterozygous mutations of TGM1 gene identified in a Chinese collodion baby]. | Zhang YL | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2012 | PMID: 22311480 |
Text-mined citations for rs139208806 ...
HelpRecord last updated Mar 17, 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.