Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255177 | SCV000321963 | likely pathogenic | not provided | 2016-05-26 | criteria provided, single submitter | clinical testing | The R396L likely pathogenic variant in the TGM1 gene has been report previously as R395L in Finnish patients diagnosed with lamellar ichthyosis and nonbullous congenital ichthyosiformis erythroderma (Laiho et al., 1997). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, per the 1000 Genomes Consortium, the R396L variant was observed with a frequency of 1.5%, 3/198 alleles, in individuals of Finnish ancestry (McVean et al., 2014). Missense variants at the same (R396S/H) and in nearby residues (G392D, F401V) have been reported in the Human Gene Mutation Database in association with lamellar ichthyosis/ autosomal recessive congenital ichthyosis (Stenson et al., 2012), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Invitae | RCV000255177 | SCV001407932 | pathogenic | not provided | 2023-03-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg396 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19500103, 23689228, 26762237, 27025581). 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: 12487). This variant is also known as Arg395Leu. This missense change has been observed in individuals with congenital ichthyosis (PMID: 9326318, 25766764, 27025581). This variant is present in population databases (rs121918721, gnomAD 0.07%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 396 of the TGM1 protein (p.Arg396Leu). |
| Genome- |
RCV000013309 | SCV002763640 | likely pathogenic | Autosomal recessive congenital ichthyosis 1 | criteria provided, single submitter | clinical testing | ||
| OMIM | RCV000013309 | SCV000033555 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 1997-09-01 | no assertion criteria provided | literature only | |
| Counsyl | RCV000013309 | SCV000793010 | likely pathogenic | Autosomal recessive congenital ichthyosis 1 | 2017-07-25 | no assertion criteria provided | clinical testing |