Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000523198 | SCV000616892 | pathogenic | not provided | 2018-07-19 | criteria provided, single submitter | clinical testing | The R389H pathogenic variant in the TGM1 gene has been reported previously either in combination with another TGM1 variant or in the homozygous state in individuals with autosomal recessive congenital ichthyosis (Akiyama et al., 2001; Esposito et al., 2014). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R389H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position in the core domain (Akiyama et al., 2001) that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense variant in the same codon (R389P) has also been reported in association with congenital ichthyosis (Schevchenko et al., 2000; Oji et al., 2006), supporting the functional importance of this region of the protein. We interpret R389H as a pathogenic variant. |
| Kariminejad - |
RCV001813979 | SCV001755248 | likely pathogenic | Abnormality of the skin | 2021-07-10 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000013311 | SCV001810238 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 2021-07-22 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000523198 | SCV002239745 | pathogenic | not provided | 2023-01-24 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Arg389 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10914678, 16968736, 19241467). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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: 12489). This variant is also known as R388H. This missense change has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 11251583, 14996130, 23278109, 27025581). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121918723, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the TGM1 protein (p.Arg389His). |
| Baylor Genetics | RCV000013311 | SCV004203736 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 2023-10-16 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000013311 | SCV000033558 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 2001-02-01 | no assertion criteria provided | literature only | |
| Counsyl | RCV000013311 | SCV000793610 | likely pathogenic | Autosomal recessive congenital ichthyosis 1 | 2017-08-25 | no assertion criteria provided | clinical testing |