ClinVar Miner

Submissions for variant NM_000359.3(TGM1):c.832G>A (p.Gly278Arg) (rs121918725)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000439800 SCV000514898 pathogenic not provided 2017-01-09 criteria provided, single submitter clinical testing The G278R pathogenic variant in the TGM1 gene has been reported previously in multiple unrelated families with lamellar ichthyosis, either in the homozygous state or in trans with a different missense variant (Cserhalmi-Friedman et al., 2001; Raghunath et al., 2003; Zhang et al., 2012; Al-Naamani et al., 2013). 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. G278R 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. A different nucleotide change also leading to G278R (c.832G>C) and a missense variant in a nearby residue (Y276N) have been reported in the Human Gene Mutation Database in association with ichthyosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional study of the G278R variant has shown that it results in reduced activity of the epidermal transglutaminase 1 protein (Raghunath et al., 2003). We interpret G278R as a pathogenic variant.
Counsyl RCV000013315 SCV000791977 likely pathogenic Autosomal recessive congenital ichthyosis 1 2017-06-02 criteria provided, single submitter clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000013315 SCV000891558 likely pathogenic Autosomal recessive congenital ichthyosis 1 2017-12-30 criteria provided, single submitter curation
Invitae RCV000439800 SCV000933752 pathogenic not provided 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 278 of the TGM1 protein (p.Gly278Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121918725, ExAC 0.006%). This variant has been observed to segregate with TGM1-related conditions in several families and has been observed in several other affected patients (PMID: 22311480, 23689228, 28403434). ClinVar contains an entry for this variant (Variation ID: 12492). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
OMIM RCV000013315 SCV000033561 pathogenic Autosomal recessive congenital ichthyosis 1 2003-02-01 no assertion criteria provided literature only
Natera, Inc. RCV000013315 SCV001459985 pathogenic Autosomal recessive congenital ichthyosis 1 2020-09-16 no assertion criteria provided clinical testing

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