Submissions for variant NM_000359.3(TGM1):c.857G>A (p.Arg286Gln)

gnomAD frequency: 0.00002  dbSNP: rs121918727

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255608	SCV000321961	pathogenic	not provided	2017-12-14	criteria provided, single submitter	clinical testing	The R286Q pathogenic variant in the TGM1 gene has been reported previously with another TGM1 variant in an individual with lamellar ichthyosis (Cserhalmi-Friedman et al., 2001). R286Q has also been observed with another pathogenic variant or in the apparent homozygous state in several unrelated patients with congenital ichthyosis referred for genetic testing at GeneDx. The R286Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R286Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R286Q as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255608	SCV002183525	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 286 of the TGM1 protein (p.Arg286Gln). This variant is present in population databases (rs121918727, gnomAD 0.007%). This missense change has been observed in individual(s) with congenital ichthyosis (PMID: 11298529, 28403434, 31168818). ClinVar contains an entry for this variant (Variation ID: 12495). 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.Arg286 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been observed in individuals with TGM1-related conditions (PMID: 30578701), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000013318	SCV002763829	pathogenic	Autosomal recessive congenital ichthyosis 1		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000013318	SCV004203753	likely pathogenic	Autosomal recessive congenital ichthyosis 1	2023-09-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000013318	SCV005629766	pathogenic	Autosomal recessive congenital ichthyosis 1	2024-03-07	criteria provided, single submitter	clinical testing
OMIM	RCV000013318	SCV000033565	pathogenic	Autosomal recessive congenital ichthyosis 1	2001-04-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003952354	SCV004769296	likely pathogenic	TGM1-related disorder	2024-02-12	no assertion criteria provided	clinical testing	The TGM1 c.857G>A variant is predicted to result in the amino acid substitution p.Arg286Gln. This variant was reported in an individual with lamellar ichthyosis (Cserhalmi-Friedman et al. 2001. PubMed ID: 11298529; Marukian et al. 2017. PubMed ID: 28403434; Simpson et al. 2019. PubMed ID: 31168818). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Of note, another missense variant, affecting the same amino acid (p.Arg286Trp), has also been reported to be causative for lamellar ichthyosis (Youssefian et al. 2019. PubMed ID: 30578701). This variant is interpreted as likely pathogenic.