ClinVar Miner

Submissions for variant NM_000359.3(TGM1):c.968G>A (p.Arg323Gln) (rs121918717)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520296 SCV000617732 pathogenic not provided 2017-09-07 criteria provided, single submitter clinical testing The R323Q variant in the TGM1 gene has been reported previously in both the homozygous and compound heterozygous state in multiple individuals with congenital ichthyosis (Esposito et al., 2013; Huber et al., 1995; Herman et al., 2009). This variant is observed in 7/50,028 alleles (0.014%) from individuals of non-Finnish European background in the ExAC dataset with no homozygous control individuals reported (Lek et al., 2016). The R323Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this substitution occurs at a position that is conserved across species. In vitro expression studies of the R323Q variant showed a marked reduced enzyme activity (Herman et al., 2009), and cultured keratinocyes from a patient compound heterozygous for R142C and R323Q had almost no TGM1 membrane enzyme activity compared to controls (Huber et al., 1995). Lastly, another missense variant in the same codon (R323W) has been reported in the Human Gene Mutation Database in association with congenital ichthyosis (Stenson et al., 2014; Herman et al., 2009), supporting the functional importance of this residue of the protein. Therefore, we interpret R323Q as a pathogenic variant.
Invitae RCV000520296 SCV000955335 pathogenic not provided 2020-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 323 of the TGM1 protein (p.Arg323Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs121918717, ExAC 0.01%). This variant has been observed to segregate with autosomal recessive congenital ichthyosis in a family (PMID: 7824952) and has also been observed in several other individuals affected with autosomal recessive congenital ichthyosis (PMID: 9545389, 23278109, 19241467). ClinVar contains an entry for this variant (Variation ID: 12484). This variant has been reported to affect TGM1 protein function (PMID:9261103, 9593710). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000013303 SCV001554489 pathogenic Autosomal recessive congenital ichthyosis 1 criteria provided, single submitter clinical testing
OMIM RCV000013303 SCV000033550 pathogenic Autosomal recessive congenital ichthyosis 1 1995-01-27 no assertion criteria provided literature only
Counsyl RCV000013303 SCV000793786 likely pathogenic Autosomal recessive congenital ichthyosis 1 2017-08-30 no assertion criteria provided clinical testing
Natera, Inc. RCV000013303 SCV001459980 pathogenic Autosomal recessive congenital ichthyosis 1 2020-09-16 no assertion criteria provided clinical testing

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