ClinVar Miner

Submissions for variant NM_000359.3(TGM1):c.919C>T (p.Arg307Trp)

dbSNP: rs121918731
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000013322 SCV000798107 likely pathogenic Autosomal recessive congenital ichthyosis 1 2018-02-26 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000795243 SCV000934691 pathogenic not provided 2023-01-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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: 16968736, 19863506, 26076875, 27025581, 28403434). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 12499). This missense change has been observed in individuals with lamellar ichthyosis and self-improving collodion ichthyosis (PMID: 11407995, 11511296, 19262603, 20167857, 21895619, 24419105). This variant is present in population databases (rs121918731, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 307 of the TGM1 protein (p.Arg307Trp).
Medical Genetics Laboratory, West China Hospital, Sichuan University RCV000013322 SCV001161452 pathogenic Autosomal recessive congenital ichthyosis 1 2020-01-17 criteria provided, single submitter in vitro The newborn's entire body was covered with a thin transparent collodion membrane. Variant c.919 C>T was evaluated to be deleterious by PolyPhen-2, PROVEAN and Mutation Taster and amino acid was highly conserved in multiple species. Additionally, in vitro functional studies indicated that TGM1 protein expression levels significantly decreased in cells with c.919 C>T mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002281703 SCV002572266 pathogenic Lamellar ichthyosis 2022-08-23 criteria provided, single submitter clinical testing Variant summary: TGM1 c.919C>T (p.Arg307Trp) results in a non-conservative amino acid change in 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 2e-05 in 248966 control chromosomes (gnomAD). c.919C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Lamellar Ichthyosis, predominantly from individuals of East Asian descent (e.g. Akiyama_2001, Muramatsu_2004, Sakai_2009, Yamamoto_2012, Yang_2001). These data indicate that the variant is very likely to be associated with disease. When TGase 1 activity was assayed in cultured keratocytes from a compound heterozygous proband and their unaffected carrier parent, there was 5% activity in the proband and 50% activity in the carrier parent, suggesting the variant may have limited functionality (Yang_2001). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000013322 SCV002763784 likely pathogenic Autosomal recessive congenital ichthyosis 1 criteria provided, single submitter clinical testing
Baylor Genetics RCV000013322 SCV004203777 pathogenic Autosomal recessive congenital ichthyosis 1 2023-07-30 criteria provided, single submitter clinical testing
OMIM RCV000013322 SCV000033569 pathogenic Autosomal recessive congenital ichthyosis 1 2001-08-01 no assertion criteria provided literature only
Natera, Inc. RCV000013322 SCV001459982 pathogenic Autosomal recessive congenital ichthyosis 1 2020-09-16 no assertion criteria provided clinical testing

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