ClinVar Genomic variation as it relates to human health

The p.Arg510X variant in TSPEAR has not been previously reported in individuals with hearing loss, but has been identified in 82/126654 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; db SNP rs201663789). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This nonsense v ariant leads to a premature termination codon at position 510, which is predicte d to lead to a truncated or absent protein. Truncating variants have been previo usly reported in two probands with hearing loss and segregated in two affected s iblings in one family (Delmaghani 2012, Sloan-Heggen 2016). However, a recent st udy has also associated truncating variants in TSPEAR, including the same varian t previously reported by Delmaghani et al, with autosomal recessive ectodermal d ysplasia without hearing loss (Peled 2016). Therefore, additional information i s needed to determine the gene-disease association and the disease mechanism. In summary, because the gene-disease association is unclear, the clinical signific ance of this variant is uncertain.

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 9 of 12). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (92 heterozygotes, 0 homozygotes). (P) 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity (ClinVar; PMID:27736875). (P) 0803 - Low previous evidence of pathogenicity in unrelated individual(s). This variant has been reported as compound heterozygous in a patient with non-syndromic oligodontia (PMID:32112661). It has also been reported as a variant of uncertain significance in ClinVar. (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

This sequence change creates a premature translational stop signal (p.Arg510*) in the TSPEAR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSPEAR are known to be pathogenic (PMID: 34042254). This variant is present in population databases (rs201663789, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with clinical features of ectodermal dysplasia and/or non-syndromic oligodontia (PMID: 32112661; Invitae). ClinVar contains an entry for this variant (Variation ID: 504870). For these reasons, this variant has been classified as Pathogenic.

The TSPEAR c.1528C>T variant is predicted to result in premature protein termination (p.Arg510*). This variant was reported in the compound heterozygous state along with a missense variant in an individual with nonsyndromic oligodontia (Song et al. 2020. PubMed ID: 32112661). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TSPEAR are expected to be pathogenic. This variant is interpreted as likely pathogenic.