Submissions for variant NM_000359.3(TGM1):c.919C>G (p.Arg307Gly)

gnomAD frequency: 0.00029  dbSNP: rs121918731

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413014	SCV000490849	pathogenic	not provided	2022-10-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant is associated with decreased activity of transglutaminase 1 (Oji et al., 2006; Aufenvenne et al., 2009); This variant is associated with the following publications: (PMID: 34908195, 16968736, 23278109, 19890349, 28488422, 27025581, 26076875, 19863506, 30693114, 30609409, 31980526, 34426522, 31589614, 19212342, 31168818)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000599792	SCV000731592	pathogenic	Lamellar ichthyosis	2017-04-14	criteria provided, single submitter	clinical testing	The p.Arg307Gly (NM_000359.2 c.919C>G) variant in TGM1 has been reported in 6 co mpound heterozygous and 1 homozygous individuals with lamellar icthyosis related conditions (self-healing collodion baby and bathing suit ichthyosis) (Oji 2006, Valquist 2010, Hackett 2010, and Pigg 2016), and segregated in 1 sibling in 1 f amily (Hackett 2010). This variant has been reported in ClinVar (Variation ID#37 2534) as pathogenic by 1 laboratory. This variant has been identified in 0.023% (14/60410) of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs121918731). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Arg307Gly variant may impact protein function (Aufenvenne 2009). In summary, this variant meets criteria to be classified as pathogenic for Lamel lar ichthyosis related conditions in an autosomal recessive manner based upon it s occurrence in individuals with this disease and functional evidence.
Fulgent Genetics, Fulgent Genetics	RCV000762928	SCV000893348	pathogenic	Autosomal recessive congenital ichthyosis 1	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000413014	SCV000958597	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 307 of the TGM1 protein (p.Arg307Gly). This variant is present in population databases (rs121918731, gnomAD 0.05%). This missense change has been observed in individuals with ichthyosis (PMID: 16968736, 19863506, 26076875, 27025581, 28403434). ClinVar contains an entry for this variant (Variation ID: 372534). 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. Experimental studies have shown that this missense change affects TGM1 function (PMID: 19212342). This variant disrupts the p.Arg307 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11407995, 11511296, 19262603, 20167857, 21895619, 24419105). 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.
Myriad Genetics, Inc.	RCV000762928	SCV001193903	pathogenic	Autosomal recessive congenital ichthyosis 1	2020-01-03	criteria provided, single submitter	clinical testing	NM_000359.2(TGM1):c.919C>G(R307G) is classified as pathogenic in the context of TGM1-related autosomal recessive congenital ichthyosis. Sources cited for classification include the following: PMID: 22801880, 16968736, 19212342, 19890349 and 26762237. Classification of NM_000359.2(TGM1):c.919C>G(R307G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000413014	SCV002497706	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	TGM1: PM3:Very Strong, PM1, PM5, PM2:Supporting, PP1, PP4, PS3:Supporting
Genome-Nilou Lab	RCV000762928	SCV002763773	pathogenic	Autosomal recessive congenital ichthyosis 1		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000762928	SCV004203730	pathogenic	Autosomal recessive congenital ichthyosis 1	2023-10-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000599792	SCV004804524	pathogenic	Lamellar ichthyosis	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: TGM1 c.919C>G (p.Arg307Gly) results in a non-conservative amino acid change in the encoded protein sequence. Another missense variant affecting this residue (p.Arg307Trp) has been classified as pathogenic. 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 0.00015 in 248966 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TGM1 causing Lamellar Ichthyosis (0.00015 vs 0.0021), allowing no conclusion about variant significance. c.919C>G has been reported in the literature in multiple individuals affected with Congenital Ichthyosis (Bourrat_2012, Diociaiuti_2016), and some were compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22801880, 26762237). ClinVar contains an entry for this variant (Variation ID: 372534). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV000762928	SCV001459983	pathogenic	Autosomal recessive congenital ichthyosis 1	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000413014	SCV001927862	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413014	SCV001953632	pathogenic	not provided		no assertion criteria provided	clinical testing