ClinVar Genomic variation as it relates to human health
NM_000359.3(TGM1):c.967C>T (p.Arg323Trp)
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(5); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000359.3(TGM1):c.967C>T (p.Arg323Trp)
Variation ID: 449108 Accession: VCV000449108.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q12 14: 24259721 (GRCh38) [ NCBI UCSC ] 14: 24728927 (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 Dec 19, 2017 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000359.3:c.967C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000350.1:p.Arg323Trp missense NC_000014.9:g.24259721G>A NC_000014.8:g.24728927G>A NG_007150.1:g.8446C>T - Protein change
- R323W
- Other names
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- Canonical SPDI
- NC_000014.9:24259720: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 | 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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Aug 5, 2023 | RCV000521059.7 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Apr 4, 2024 | RCV000671220.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2022 | RCV002271520.1 |
Submissions - Germline
Classification
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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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Uncertain significance
(Dec 04, 2017)
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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: SCV000796173.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318848.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TGM1 related disorder (PMID:19241467). A different missense change … (more)
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TGM1 related disorder (PMID:19241467). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012484, PMID:7824952,32573669). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.898>=0.6, 3CNET: 0.998>=0.75). A missense variant is a common mechanism . It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000163). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Congenital nonbullous ichthyosiform erythroderma (present)
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Pathogenic
(Jun 30, 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: SCV002556264.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: TGM1 c.967C>T (p.Arg323Trp) 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.967C>T (p.Arg323Trp) 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 1.6e-05 in 245428 control chromosomes (gnomAD). c.967C>T has been reported in the literature in individuals affected with Ichthyosis, including at least two cases where it has been found in trans with a pathogenic variant and one homozygous case (e.g. Herman_2009, Simpson_2020, Cheng_2020). These data indicate that the variant is likely to be associated with disease. This variant results in an amino acid change at the same position as another variant, c.968G>A (p.Arg323Gln), that has been classified as pathogenic with strong supporting evidence (ClinVar: 12484), suggesting this site may be important for normal protein function. To our knowledge, this has yet to be investigated by functional studies. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as likely pathogenic, one as pathogenic, and one classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 06, 2023)
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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: SCV000616891.3
First in ClinVar: Dec 19, 2017 Last updated: Apr 15, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31168818, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31168818, 31953843, 19241467, 23278109) (less)
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Pathogenic
(Feb 25, 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: SCV004203808.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Aug 05, 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: SCV002238029.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Arg323 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7824952, 9261103, … (more)
This variant disrupts the p.Arg323 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7824952, 9261103, 9545389, 23278109). 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) performed at Invitae indicates that this missense variant is expected to disrupt TGM1 protein function. ClinVar contains an entry for this variant (Variation ID: 449108). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 19241467, 31168818, 31953843). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 323 of the TGM1 protein (p.Arg323Trp). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 04, 2024)
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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 Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809377.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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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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Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System. | Australian Genomics Health Alliance Acute Care Flagship | JAMA | 2020 | PMID: 32573669 |
Next-generation sequencing through multi-gene panel testing for diagnosis of hereditary ichthyosis in Chinese. | Cheng R | Clinical genetics | 2020 | PMID: 31953843 |
Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis. | Simpson JK | The British journal of dermatology | 2020 | PMID: 31168818 |
Different TGM1 mutation spectra in Italian and Portuguese patients with autosomal recessive congenital ichthyosis: evidence of founder effects in Portugal. | Esposito G | The British journal of dermatology | 2013 | PMID: 23278109 |
Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: summary of mutations (including 23 novel) and modeling of TGase-1. | Herman ML | Human mutation | 2009 | PMID: 19241467 |
Genotype/phenotype correlation in autosomal recessive lamellar ichthyosis. | Hennies HC | American journal of human genetics | 1998 | PMID: 9545389 |
Consequences of seven novel mutations on the expression and structure of keratinocyte transglutaminase. | Huber M | The Journal of biological chemistry | 1997 | PMID: 9261103 |
Mutations of keratinocyte transglutaminase in lamellar ichthyosis. | Huber M | Science (New York, N.Y.) | 1995 | PMID: 7824952 |
Text-mined citations for rs771820315 ...
HelpRecord last updated Apr 15, 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.