Submissions for variant NM_000359.3(TGM1):c.377G>A (p.Arg126His)

gnomAD frequency: 0.00004  dbSNP: rs200491579

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000329115	SCV000329546	pathogenic	not provided	2019-12-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R126H results in absent transglutaminase-1 enzyme activity (Aufenvenne et al., 2012; Aufenvenne et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31168818, 22437313, 24055110, 25998749, 31046801, 18948357, 31980526, 31589614)
Invitae	RCV000329115	SCV001585871	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 126 of the TGM1 protein (p.Arg126His). This variant is present in population databases (rs200491579, gnomAD 0.006%). This missense change has been observed in individuals with congenital ichthyosis (PMID: 19241467, 22437313, 31046801, 31168818). ClinVar contains an entry for this variant (Variation ID: 279909). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TGM1 protein function. This variant disrupts the p.Arg126 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 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.
Genome-Nilou Lab	RCV000673549	SCV002764062	pathogenic	Autosomal recessive congenital ichthyosis 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226271	SCV003922636	pathogenic	Lamellar ichthyosis	2023-03-02	criteria provided, single submitter	clinical testing	Variant summary: TGM1 c.377G>A (p.Arg126His) 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 3.6e-05 in 251210 control chromosomes (gnomAD). c.377G>A has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis (e.g. Farasat_2008, Herman_2009, Aufenvenne_2012, Borska_2019, Simpson_2020). At least one of these publications reported the lack of TG1 protein and activity in patient derived skin biopsy samples (Aufenvenne_2012). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=3) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000673549	SCV004203728	pathogenic	Autosomal recessive congenital ichthyosis 1	2023-10-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000673549	SCV000798763	likely pathogenic	Autosomal recessive congenital ichthyosis 1	2018-03-23	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000673549	SCV002091240	pathogenic	Autosomal recessive congenital ichthyosis 1	2020-09-15	no assertion criteria provided	clinical testing