Submissions for variant NM_000359.3(TGM1):c.1186C>T (p.Arg396Cys)

gnomAD frequency: 0.00001  dbSNP: rs543521135

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Uitto Lab, Thomas Jefferson University	RCV000782372	SCV000920893	likely pathogenic	Autosomal recessive congenital ichthyosis 1	2018-06-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001576631	SCV001803860	pathogenic	not provided	2020-06-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30578701)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805848	SCV002051227	likely pathogenic	Lamellar ichthyosis	2021-12-18	criteria provided, single submitter	clinical testing	Variant summary: TGM1 c.1186C>T (p.Arg396Cys) results in a non-conservative amino acid change located in the Transglutaminase-like domain (IPR002931) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A recent study using structural modeling, molecular docking and molecular dynamics approaches concluded that missense variants in the Transglut_core domain of TGM1 are deleterious to the stability and structural changes of the TGM1 protein (Nasser_2020). The variant allele was found at a frequency of 8e-06 in 251310 control chromosomes. c.1186C>T has been reported in the literature as a homozygous genotype in at-least one individual from a consanguineous union affected with Lamellar Ichthyosis (example, Youssefian_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000782372	SCV002072909	likely pathogenic	Autosomal recessive congenital ichthyosis 1		criteria provided, single submitter	clinical testing	The missense variant p.R396C in TGM1 (NM_000359.3) has been previously submitted to ClinVar as Pathogenic, however no details are available for independent assessment. It has been reported in individuals with icthyosis (Nasser KK et al). Other missense mutations affecting the same amino acid have been reported previously (R396S, R396L). The p.R396C variant is observed in 2/30,616 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and in 1/978 (0.1022%) alleles from individuals of South Asian background in 1000 Genomes. The p.R396C missense variant is predicted to be damaging by both SIFT and PolyPhen2.The arginine residue at codon 396 of TGM1 is conserved in all mammalian species. The nucleotide c.1186 in TGM1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab	RCV000782372	SCV002763651	likely pathogenic	Autosomal recessive congenital ichthyosis 1		criteria provided, single submitter	clinical testing
Invitae	RCV001576631	SCV003483474	likely pathogenic	not provided	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 396 of the TGM1 protein (p.Arg396Cys). This variant is present in population databases (rs543521135, gnomAD 0.006%). This missense change has been observed in individual(s) with lamellar ichthyosis (PMID: 30578701). ClinVar contains an entry for this variant (Variation ID: 633787). 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. This variant disrupts the p.Arg396 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9326318, 25766764, 27025581; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Natera, Inc.	RCV000782372	SCV002091221	pathogenic	Autosomal recessive congenital ichthyosis 1	2021-04-27	no assertion criteria provided	clinical testing