ClinVar Miner

Submissions for variant NM_201631.4(TGM5):c.337G>T (p.Gly113Cys) (rs112292549)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000340380 SCV000329549 pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing The G113C variant in the TGM5 gene has been reported previously in both the homozygous and compound heterozygous state in numerous individuals with acral peeling skin syndrome (APSS) (Cassidy et al., 2005; Kiritsi et al., 2010; Pigors et al., 2012; Kavaklieva et al., 2013; van der Velden et al., 2015). The G113C variant is observed in 460/126,578 alleles (0.36%) from individuals of non-Finnish European background, and 660/277,002 global alleles (0.24%) including two homozygous control individuals, in large population cohorts (Lek et al., 2016), consistent with the high carrier frequency reported in controls in other studies (Pigors et al., 2012). The G113C 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. In addition, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Although no other pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with APSS (Stenson et al., 2014), in vitro studies have shown that G113C completely abolishes cross-linking activity of the enzyme in transfected epithelial cell lines (Cassidy et al 2005). In summary, we interpret G113C as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000006411 SCV000391245 pathogenic Peeling skin syndrome 2 2017-10-18 criteria provided, single submitter clinical testing Across a selection of the available literature, the TGM5 c.337G>T (p.Gly113Cys) missense variant, which is a founder variant in the European population, was reported in at least 97 patients, including in a homozygous state in at least 91 patients with peeling skin syndrome, in a compound heterozygous state in at least six patients, and in a heterozygous state in six unaffected parents of patients (Cassidy et al. 2005; Kiritsi et al. 2010; van der Velden et al. 2012; Pigors et al. 2012; Kavaklieva et al. 2013; Szczecinska et al. 2014; Kopečková et al. 2016). The variant was identified in a heterozygous state in four out of 250 controls and is reported at a frequency of 0.00454 in the European American population of the Exome Sequencing Project. This frequency is higher than expected based on disease prevalence estimates, but may be consistent with under-diagnosis and with the fact that this is a common founder variant. Cassidy et al. (2005) measured enzyme activity for the p.Gly113Cys variant in two different epithelial cell lines and demonstrated that the variant completely abolished activity. Based on the collective evidence, the p.Gly113Cys variant is classified as pathogenic for peeling skin syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Ambry Genetics RCV000623924 SCV000741601 pathogenic Inborn genetic diseases 2016-10-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
CeGaT Praxis fuer Humangenetik Tuebingen RCV000340380 SCV001249030 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
OMIM RCV000006411 SCV000026594 pathogenic Peeling skin syndrome 2 2012-10-01 no assertion criteria provided literature only
GeneReviews RCV000006411 SCV000322809 pathogenic Peeling skin syndrome 2 2016-10-13 no assertion criteria provided literature only

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