Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000032731 | SCV000790243 | likely pathogenic | Autosomal recessive congenital ichthyosis 1 | 2017-03-09 | criteria provided, single submitter | clinical testing | |
Department Of Genetics, |
RCV000032731 | SCV000891665 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 2017-12-30 | criteria provided, single submitter | curation | |
Invitae | RCV001038244 | SCV001201708 | pathogenic | not provided | 2024-01-11 | 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 396 of the TGM1 protein (p.Arg396His). This variant is present in population databases (rs121918721, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 19500103, 23689228, 26762237, 27025581). 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: 39533). 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: 19500103). For these reasons, this variant has been classified as Pathogenic. |
Genome- |
RCV000032731 | SCV002763577 | likely pathogenic | Autosomal recessive congenital ichthyosis 1 | criteria provided, single submitter | clinical testing | ||
Center for Genomics, |
RCV000032731 | SCV003920557 | 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 homozygous or compound heterozygous states in more than 10 individuals with features consistent with congenital ichthyosis, segregating with disease in at least 4 similarly affected family members (Selected publications: Mazereeuw-Hautier 2009 PMID: 18948357; Rodríguez-Pazos 2011 PMID: 21668430; Al-Naamani 2013 PMID: 23689228; Zambrano 2014 PMID: 24261627; Pigg 2016 PMID: 27025581). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.01% [2/15272]; https://gnomad.broadinstitute.org/variant/14-24258646-C-T?dataset=gnomad_r3); 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: 39533). In vitro functional studies suggest that this variant significantly impairs the encoded protein's enzymatic activity (Mazereeuw-Hautier 2009 PMID: 18948357); however, these studies may not accurately represent in vivo biological function. Evolutionary conservation and computational prediction tools similarly strongly suggest that this variant impacts the protein. Furthermore, different variants at the same amino acid position (p.Arg396Cys, p.Arg396Leu, p.Arg396Ser) have all been reported in association with disease in the literature and in ClinVar (Variation IDs: 12487, 633787), further supporting the functional significance of this amino acid position. In summary, this variant is classifed as pathogenic. |
Baylor Genetics | RCV000032731 | SCV004203780 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 2023-07-24 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000032731 | SCV000056495 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 2009-08-01 | no assertion criteria provided | literature only | |
Natera, |
RCV000032731 | SCV002091220 | pathogenic | Autosomal recessive congenital ichthyosis 1 | 2020-08-25 | no assertion criteria provided | clinical testing |