Submissions for variant NM_000359.3(TGM1):c.1417G>A (p.Gly473Ser)

gnomAD frequency: 0.00001  dbSNP: rs904122716

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413793	SCV000490853	pathogenic	not provided	2015-08-11	criteria provided, single submitter	clinical testing	The G473S pathogenic variant has been reported in multiple individuals with LI who were either homozygous or compound heterozygous for G473S and a second variant on the other allele (Huber et al., 1997; Terrinoni et al., 2012). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G473S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in-silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, functional studies of G473S have shown that it results in reduced protein levels and activity (Huber et al., 1997). Therefore, we interpret G473S as a pathogenic variant.
Fulgent Genetics, Fulgent Genetics	RCV000762927	SCV000893345	likely pathogenic	Autosomal recessive congenital ichthyosis 1	2018-10-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000762927	SCV002763207	likely pathogenic	Autosomal recessive congenital ichthyosis 1		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000762927	SCV004203775	pathogenic	Autosomal recessive congenital ichthyosis 1	2023-08-04	criteria provided, single submitter	clinical testing
Invitae	RCV000413793	SCV004296318	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 473 of the TGM1 protein (p.Gly473Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with lamellar ichthyosis (PMID: 9261103, 23096117). ClinVar contains an entry for this variant (Variation ID: 372536). 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 with a positive predictive value of 95%. This variant disrupts the p.Gly473 amino acid residue in TGM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 35412663). 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.