rs112292549
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBP4
The NM_201631.4(TGM5):c.337G>T(p.Gly113Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,614,140 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_201631.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00242 AC: 369AN: 152176Hom.: 1 Cov.: 31
GnomAD3 exomes AF: 0.00235 AC: 589AN: 251022Hom.: 2 AF XY: 0.00247 AC XY: 335AN XY: 135830
GnomAD4 exome AF: 0.00286 AC: 4181AN: 1461846Hom.: 13 Cov.: 32 AF XY: 0.00281 AC XY: 2043AN XY: 727232
GnomAD4 genome AF: 0.00242 AC: 369AN: 152294Hom.: 1 Cov.: 31 AF XY: 0.00251 AC XY: 187AN XY: 74470
ClinVar
Submissions by phenotype
Acral peeling skin syndrome Pathogenic:9Other:1
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PM3_strong, PS3, PP1, PP3 -
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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; KopeÄková 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. -
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Criteria applied: PM3_VSTR,PS3_SUP,PP3 -
This sequence change in TGM5 is predicted to replace glycine with cysteine at codon 113, p.(Gly113Cys). The glycine residue is highly conserved (100 vertebrates, Multiz Alignments), and is not located in the beta-sandwich domain (PMID: 24628291). There is a large physicochemical difference between glycine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.3% (3,945/1,180,028 alleles, 10 homozygotes) in the European (non-Finnish) population, which is higher than expected for a recessive condition. This variant is commonly reported in the European population in individuals with TGM5-related peeling skin syndrome and segregates with disease in at least one family (PMID: 16380904). This variant has been detected as homozygous and compound heterozygous in multiple individuals with peeling skin syndrome, with at least one pathogenic variant confirmed on the second allele (PMID: 24628291). A functional study with limited validation assaying TG5 enzyme activity is supportive of a damaging effect on protein function (PMID: 16380904). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.90) and no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PP3, PS3_Supporting, BS1. -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene and is associated with peeling skin syndrome 2 (MIM#609796). (I) 0106 - This gene is known to be associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (657 heterozygotes, 2 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated N-terminal transglutaminase domain (NCBI). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as homozygous and compound heterozygous in individuals with peeling skin syndrome (ClinVar, PMID: 29242947). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected cell lines displayed complete loss of enzyme activity (PMID: 16380904). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:4
TGM5: PM3:Very Strong, PM2:Supporting, PP4, PS3:Supporting -
Common variant identified especially in individuals of Northern European descent (Lek et al., 2016); Published functional studies demonstrate that G113C completely abolishes cross-linking activity of the enzyme in transfected epithelial cell lines (Cassidy et al., 2005; van der Velden et al., 2015); This variant is associated with the following publications: (PMID: 16380904, 24019772, 27206604, 26707537, 30688214, 31028847, 20301543, 20220177, 19440220, 22622422, 25510201, 26684698, 22429841, 24628291, 29242947, 31001817, 31980526, 25644735, 20164844, 31589614) -
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PM3, PS3, PP4, PP3, PS4 -
Inborn genetic diseases Pathogenic:1
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TGM5-related disorder Pathogenic:1
The TGM5 c.337G>T variant is predicted to result in the amino acid substitution p.Gly113Cys. This variant, in either the homozygous or compound heterozygous states with a second pathogenic variant, has been reported to be causative for acral peeling skin syndrome in multiple unrelated families (Cassidy et al. 2005. PubMed ID: 16380904; Kiritsi et al. 2010. PubMed ID: 20164844; Pigors et al. 2012. PubMed ID: 22622422; Kavaklieva et al. 2013. PubMed ID: 24019772; van der Velden et al 2015. PubMed ID: 25644735; Has et al. 2018. PubMed ID: 29242947). This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at