ClinVar Miner

Submissions for variant NM_000359.3(TGM1):c.1075G>A (p.Val359Met)

gnomAD frequency: 0.00001  dbSNP: rs202037016
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000032730 SCV000800493 uncertain significance Autosomal recessive congenital ichthyosis 1 2017-02-03 criteria provided, single submitter clinical testing
Invitae RCV002514137 SCV003442324 likely pathogenic not provided 2023-08-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 359 of the TGM1 protein (p.Val359Met). This variant is present in population databases (rs202037016, gnomAD 0.0009%). This missense change has been observed in individuals with congenital ichthyosis ( (PMID: 19241467, 19500103). ClinVar contains an entry for this variant (Variation ID: 39532). 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. Experimental studies have shown that this missense change affects TGM1 function (PMID: 19500103). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003317053 SCV004020584 uncertain significance not specified 2023-06-03 criteria provided, single submitter clinical testing Variant summary: TGM1 c.1075G>A (p.Val359Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251160 control chromosomes. c.1075G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with features of Autosomal recessive congenital ichthyosis (ARCI) or a novel phenotype of acral self-healing collodion baby (example, Herman_2009, Mazereeuw-Hautier_2009). The case report describing the novel phenotype of acral self-healing collodion baby reports its presence in a family with three segregating variants in the TGM1 gene (Mazereeuw-Hautier_2009). The proband was compound heterozygous for this paternally inherited variant and a maternally inherited p.Arg396His variant. While the sister was compound heterozygous for a different paternally inherited variant (c.1922_1926+2delGGCCTGT) and maternally inherited p.Arg396His variant seen in her proband sibling. The father who carries the deletion and the p.Val359Met mutation was reported as having no clinical symptoms, although the authors did not rule out the possibility that he was not aware of a very transient and mild anomaly of his skin at birth.. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Mazereeuw-Hautier_2009). The most pronounced variant effect results in 12.8% of normal recombinant transglutaminase enzyme activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 19241467, 19500103). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Both labs cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV000032730 SCV004203799 likely pathogenic Autosomal recessive congenital ichthyosis 1 2023-04-11 criteria provided, single submitter clinical testing
OMIM RCV000032730 SCV000056494 pathogenic Autosomal recessive congenital ichthyosis 1 2009-08-01 no assertion criteria provided literature only

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