ClinVar Miner

Submissions for variant NM_000359.3(TGM1):c.1187G>A (p.Arg396His)

dbSNP: rs121918721
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Total submissions: 8
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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, Sultan Qaboos University Hospital, Sultan Qaboos University 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-Nilou Lab RCV000032731 SCV002763577 likely pathogenic Autosomal recessive congenital ichthyosis 1 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago 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, Inc. RCV000032731 SCV002091220 pathogenic Autosomal recessive congenital ichthyosis 1 2020-08-25 no assertion criteria provided clinical testing

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