ClinVar Miner

Submissions for variant NM_201631.4(TGM5):c.255del (p.Ser86fs) (rs778322388)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778431 SCV000914676 likely pathogenic Peeling skin syndrome 2 2018-11-12 criteria provided, single submitter clinical testing The TGM5 c.255delC (p.Ser86AlafsTer17) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Ser86AlafsTer17 variant is reported in two studies in which it is found in a compound heterozygous state in three patients including two brothers, all diagnosed with peeling skin syndrome. The two brothers carried the variant in trans with a deletion variant in the splice donor site of intron 7, while the third individual carried the variant in trans with a missense variant (Szczecinska et al 2014; van der Velden et al. 2015). Control data are not available for this variant which is reported at a frequency of 0.002087 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence and potential impact of stop-gained variants, the p.Ser86AlafsTer17 is classified as likely pathogenic for peeling skin syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV001008784 SCV001168576 pathogenic not provided 2019-08-23 criteria provided, single submitter clinical testing The c.255delC pathogenic variant in the TGM5 gene has been reported previously in combination with a second TGM5 variant in individuals with acral peeling skin syndrome (van der Velden et al., 2015, Szczecinska et al., 2014). The c.255delC variant causes a frameshift starting with codon Serine 86, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Ser86AlafsX17. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.255delC variant is observed in 21/9,844 (0.21%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). We interpret c.255delC as a pathogenic variant.

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