NM_000359.3(TGM1):c.788G>A (p.Trp263Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 27, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000483411.6

Allele description [Variation Report for NM_000359.3(TGM1):c.788G>A (p.Trp263Ter)]

NM_000359.3(TGM1):c.788G>A (p.Trp263Ter)

Gene:

TGM1:transglutaminase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q12

Genomic location:

Preferred name:

NM_000359.3(TGM1):c.788G>A (p.Trp263Ter)

HGVS:

NC_000014.9:g.24260028C>T
NG_007150.1:g.8139G>A
NM_000359.3:c.788G>AMANE SELECT
NP_000350.1:p.Trp263Ter
NC_000014.8:g.24729234C>T
NM_000359.2:c.788G>A

Protein change:

W263*

Links:

dbSNP: rs367699137

NCBI 1000 Genomes Browser:

rs367699137

Molecular consequence:

NM_000359.3:c.788G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000567180	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jul 15, 2015)	germline	clinical testing	Citation Link,
SCV000947607	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 27, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18948357, 19241467, 23192619, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000567180

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jul 15, 2015)

germline

clinical testing

Citation Link,

SCV000947607

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 27, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA.

Farasat S, Wei MH, Herman M, Liewehr DJ, Steinberg SM, Bale SJ, Fleckman P, Toro JR.

J Med Genet. 2009 Feb;46(2):103-11. doi: 10.1136/jmg.2008.060905. Epub 2008 Oct 23.

PubMed [citation]

PMID:: 18948357
PMCID:: PMC3044481

Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: summary of mutations (including 23 novel) and modeling of TGase-1.

Herman ML, Farasat S, Steinbach PJ, Wei MH, Toure O, Fleckman P, Blake P, Bale SJ, Toro JR.

Hum Mutat. 2009 Apr;30(4):537-47. doi: 10.1002/humu.20952. Review.

PubMed [citation]

PMID:: 19241467
PMCID:: PMC3243309

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000567180.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The W263X variant in the TGM1 gene has been reported previously in patients of Tunisian, Portugese, and Moroccan ancestry in association with lamellar ichthyosis (Hennies et al., 1998; Louhichi et al., 2013; Esposito et al., 2013). It is suggested that the W263X variant may be a recurrent variant in patients with severe LI of Tunisian ancestry and haplotype analysis has shown consistency with founder effects (Louichi et al., 2013; Esposito et al., 2013). W263X was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, decreased protein production due to the W263X variant results in loss of the catalytic triad of the transamidation catalytic core domain (Cserhalmi-Friedman et al., 2000; Terrinoni et al., 2012). Therefore, we consider the W263X variant to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000947607.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Trp263*) in the TGM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TGM1 are known to be pathogenic (PMID: 18948357, 19241467). This variant is present in population databases (rs367699137, ExAC 0.002%). This premature translational stop signal has been observed in individuals with congenital lamellar ichthyosis (PMID: 23192619). ClinVar contains an entry for this variant (Variation ID: 419403). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 30, 2023

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