ClinVar Genomic variation as it relates to human health
NM_000359.3(TGM1):c.919C>T (p.Arg307Trp)
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.919C>T (p.Arg307Trp)
Variation ID: 12499 Accession: VCV000012499.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q12 14: 24259769 (GRCh38) [ NCBI UCSC ] 14: 24728975 (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 22, 2016 Feb 14, 2024 Jul 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000359.3:c.919C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000350.1:p.Arg307Trp missense NC_000014.9:g.24259769G>A NC_000014.8:g.24728975G>A NG_007150.1:g.8398C>T P22735:p.Arg307Trp - Protein change
- R307W
- Other names
- R306W
- Canonical SPDI
- NC_000014.9:24259768:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein Variation Ontology [VariO:0002]
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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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0.00040 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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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TGM1 | - | - |
GRCh38 GRCh38 GRCh37 |
968 | - |
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
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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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jul 30, 2023 | RCV000013322.29 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2023 | RCV000795243.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 23, 2022 | RCV002281703.2 |
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
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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Pathogenic
(Aug 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lamellar ichthyosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572266.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: TGM1 c.919C>T (p.Arg307Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: TGM1 c.919C>T (p.Arg307Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248966 control chromosomes (gnomAD). c.919C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Lamellar Ichthyosis, predominantly from individuals of East Asian descent (e.g. Akiyama_2001, Muramatsu_2004, Sakai_2009, Yamamoto_2012, Yang_2001). These data indicate that the variant is very likely to be associated with disease. When TGase 1 activity was assayed in cultured keratocytes from a compound heterozygous proband and their unaffected carrier parent, there was 5% activity in the proband and 50% activity in the carrier parent, suggesting the variant may have limited functionality (Yang_2001). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (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: SCV002763784.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Jan 08, 2023)
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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: SCV000934691.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg307 amino acid residue in TGM1. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg307 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16968736, 19863506, 26076875, 27025581, 28403434). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 12499). This missense change has been observed in individuals with lamellar ichthyosis and self-improving collodion ichthyosis (PMID: 11407995, 11511296, 19262603, 20167857, 21895619, 24419105). This variant is present in population databases (rs121918731, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 307 of the TGM1 protein (p.Arg307Trp). (less)
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Likely pathogenic
(Feb 26, 2018)
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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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Counsyl
Accession: SCV000798107.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
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Pathogenic
(Jan 17, 2020)
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criteria provided, single submitter
Method: in vitro
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Autosomal recessive congenital ichthyosis 1
(Autosomal recessive inheritance)
Affected status: not applicable
Allele origin:
not applicable
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Medical Genetics Laboratory, West China Hospital, Sichuan University
Accession: SCV001161452.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
Comment:
The newborn's entire body was covered with a thin transparent collodion membrane. Variant c.919 C>T was evaluated to be deleterious by PolyPhen-2, PROVEAN and Mutation … (more)
The newborn's entire body was covered with a thin transparent collodion membrane. Variant c.919 C>T was evaluated to be deleterious by PolyPhen-2, PROVEAN and Mutation Taster and amino acid was highly conserved in multiple species. Additionally, in vitro functional studies indicated that TGM1 protein expression levels significantly decreased in cells with c.919 C>T mutation. (less)
Result:
We compared expression of mutant TGM1 proteins and WT by immunoblotting. TGM1 protein expression levels significantly decreased in cells with c.919 C>T mutation.
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Pathogenic
(Jul 30, 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: SCV004203777.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Aug 01, 2001)
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no assertion criteria provided
Method: literature only
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ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 1, WITH BATHING SUIT DISTRIBUTION
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033569.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
For discussion of the arg306-to-trp (R306W) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital … (more)
For discussion of the arg306-to-trp (R306W) mutation in the TGM1 gene that was found in compound heterozygous state in a patient with autosomal recessive congenital ichthyosis primarily affecting the trunk (ARCI1; 242300) by Yang et al. (2001), see 190195.0021. In a 56-year-old Japanese woman with a mild form of lamellar ichthyosis limited to the neck, abdomen, center of the back, and bilateral axillae, Akiyama et al. (2001) identified compound heterozygosity for 2 missense mutations in the TGM1 gene, a 3404C-T transition in exon 6, resulting in an arg306-to-trp (R306W) substitution and a 2582T-A transversion in exon 4, resulting in a leu204-to-gln (L204Q; 190195.0028) substitution. The patient's mother was heterozygous for the R306W mutation; DNA was unavailable from her deceased father. Neither mutation was found in 25 unrelated Japanese controls. Immunofluorescence demonstrated reduced expression of TGM1 in the granular layer of the patient's epidermis, with normal expression of TGM3. Considering the distribution pattern of the skin lesions and the clinical history that the affected areas enlarged in the summer and became smaller in the winter, Akiyama et al. (2001) suggested that increased water content and elevated pH in the stratum corneum might play an important role in formation of lamellar scales in this patient. (less)
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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: SCV001459982.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein
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Medical Genetics Laboratory, West China Hospital, Sichuan University
Accession: SCV001161452.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Expanding the Genotypic Spectrum of Bathing Suit Ichthyosis. | Marukian NV | JAMA dermatology | 2017 | PMID: 28403434 |
Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia: Clinical Characteristics and Novel and Recurrent Mutations in 132 Patients. | Pigg MH | Acta dermato-venereologica | 2016 | PMID: 27025581 |
Prenatal Screening for Bathing-suit Ichthyosis After Diagnosis in an Older Sibling. | Mir-Bonafé JF | Actas dermo-sifiliograficas | 2015 | PMID: 26076875 |
Novel TGM1 missense mutation p.Arg727Gln in a case of self-healing collodion baby. | Tanahashi K | Acta dermato-venereologica | 2014 | PMID: 24419105 |
Bathing suit ichthyosis with summer exacerbation: a temperature-sensitive case. | Yamamoto M | The British journal of dermatology | 2012 | PMID: 21895619 |
Transglutaminase1 preferred substrate peptide K5 is an efficient tool in diagnosis of lamellar ichthyosis. | Akiyama M | The American journal of pathology | 2010 | PMID: 20167857 |
Genotype-phenotype correlations with TGM1: clustering of mutations in the bathing suit ichthyosis and self-healing collodion baby variants of lamellar ichthyosis. | Hackett BC | The British journal of dermatology | 2010 | PMID: 19863506 |
ABCA12 is a major causative gene for non-bullous congenital ichthyosiform erythroderma. | Sakai K | The Journal of investigative dermatology | 2009 | PMID: 19262603 |
Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype. | Oji V | Human molecular genetics | 2006 | PMID: 16968736 |
A Japanese patient with a mild form of lamellar ichthyosis harbouring two missense mutations in the core domain of the transglutaminase 1 gene. | Muramatsu S | The British journal of dermatology | 2004 | PMID: 14996130 |
Novel mutations of the transglutaminase 1 gene in lamellar ichthyosis. | Yang JM | The Journal of investigative dermatology | 2001 | PMID: 11511296 |
Compound heterozygous TGM1 mutations including a novel missense mutation L204Q in a mild form of lamellar ichthyosis. | Akiyama M | The Journal of investigative dermatology | 2001 | PMID: 11407995 |
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Text-mined citations for rs121918731 ...
HelpRecord last updated Feb 20, 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.