ClinVar Miner

Submissions for variant NM_000359.3(TGM1):c.420A>G (p.Ile140Met)

gnomAD frequency: 0.00008  dbSNP: rs139208806
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414724 SCV000491276 likely pathogenic not provided 2016-06-06 criteria provided, single submitter clinical testing 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.
Revvity Omics, Revvity Omics RCV001275151 SCV002016880 likely pathogenic Autosomal recessive congenital ichthyosis 1 2021-05-06 criteria provided, single submitter clinical testing
Invitae RCV000414724 SCV002147796 pathogenic not provided 2024-01-19 criteria provided, single submitter clinical testing 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.
Genetics and Molecular Pathology, SA Pathology RCV001275151 SCV002556846 likely pathogenic Autosomal recessive congenital ichthyosis 1 2022-07-04 criteria provided, single submitter clinical testing 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).
Genome-Nilou Lab RCV001275151 SCV002764006 likely pathogenic Autosomal recessive congenital ichthyosis 1 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001275151 SCV002782342 likely pathogenic Autosomal recessive congenital ichthyosis 1 2022-02-25 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001275151 SCV003920558 likely pathogenic Autosomal recessive congenital ichthyosis 1 2022-10-11 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV001275151 SCV004203726 likely pathogenic Autosomal recessive congenital ichthyosis 1 2023-10-29 criteria provided, single submitter clinical testing
Natera, Inc. RCV001275151 SCV001459989 likely pathogenic Autosomal recessive congenital ichthyosis 1 2020-09-16 no assertion criteria provided clinical testing

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