ClinVar Miner

Submissions for variant NM_000359.3(TGM1):c.424C>T (p.Arg142Cys)

gnomAD frequency: 0.00001  dbSNP: rs121918716
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000013301 SCV000792874 likely pathogenic Autosomal recessive congenital ichthyosis 1 2017-07-19 criteria provided, single submitter clinical testing
Invitae RCV000807794 SCV000947868 pathogenic not provided 2022-12-11 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects TGM1 function (PMID: 20663883, 22258055). 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: 12483). This missense change has been observed in individuals with autosomal recessive congenital ichthyosis syndromes (PMID: 7824952, 9326318, 24314425, 26076875). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 142 of the TGM1 protein (p.Arg142Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001778651 SCV002014973 pathogenic Lamellar ichthyosis 2021-10-19 criteria provided, single submitter clinical testing Variant summary: TGM1 c.424C>T (p.Arg142Cys) 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 was absent in 251442 control chromosomes. c.424C>T has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis (example, Huber_1995, Laiho_1999, Mir-Bonafe_2015). 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. The most pronounced variant effect results in <10% of normal Transglutaminase enzyme activity in vitro (example, Huber_1997). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000013301 SCV002763995 likely pathogenic Autosomal recessive congenital ichthyosis 1 criteria provided, single submitter clinical testing
Baylor Genetics RCV000013301 SCV004203812 pathogenic Autosomal recessive congenital ichthyosis 1 2024-01-01 criteria provided, single submitter clinical testing
OMIM RCV000013301 SCV000033548 pathogenic Autosomal recessive congenital ichthyosis 1 1997-09-01 no assertion criteria provided literature only
Natera, Inc. RCV000013301 SCV002091236 pathogenic Autosomal recessive congenital ichthyosis 1 2020-08-13 no assertion criteria provided clinical testing

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