Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000013304 | SCV000789571 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 2017-02-08 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001055476 | SCV001219870 | pathogenic | not provided | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 142 of the TGM1 protein (p.Arg142His). This variant is present in population databases (rs121918718, gnomAD 0.008%). This missense change has been observed in individuals with ichthyosis (PMID: 7773290, 19278426). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12485). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGM1 function (PMID: 9593710, 19212342). This variant disrupts the p.Arg142 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7824952, 9326318, 20663883, 22258055, 24314425, 26076875). 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. |
| Kariminejad - |
RCV001813977 | SCV001755307 | likely pathogenic | Abnormality of the skin | 2021-07-10 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000013304 | SCV002763984 | likely pathogenic | Autosomal recessive congenital ichthyosis 1 | criteria provided, single submitter | clinical testing | ||
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003398494 | SCV004121791 | pathogenic | Lamellar ichthyosis | 2023-10-18 | criteria provided, single submitter | clinical testing | Variant summary: TGM1 c.425G>A (p.Arg142His) results in a non-conservative amino acid change located in the transglutaminase, N-terminal domain (IPR001102) of 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 3.2e-05 in 251442 control chromosomes. c.425G>A has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis and has been found to segregate with the disease phenotype in at least one family (e.g. Russell_1995, Farasat_2009, Cheng_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found that the variant had 20% activity versus the WT protein in the cytosol and undetectable membrane-bound activity (e.g. Candi_1998). Additionally, another variant affecting the same codon (p.Arg142Cys) has been classified as pathogenic, further supporting that Arg142 is important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 9593710, 31953843, 18948357, 7773290). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000013304 | SCV004203748 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 2024-03-02 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000013304 | SCV000033551 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 1997-09-01 | no assertion criteria provided | literature only |