ClinVar Genomic variation as it relates to human health

The SH3TC2 c.505T>C; p.Tyr169His variant (rs80359890) is reported in the literature in several families affected with Charcot-Marie-Tooth (CMT) disease (Lassuthova 2011, Lupski 2013), While this variant was found in trans to a pathogenic variant in one individual (Lassuthova 2011), it was found in cis to a start-loss variant in a different family (Lupski 2013). The p.Tyr169His variant is found in the non-Finnish European population with an overall allele frequency of 0.31% (403/129164 alleles, including one homozygotes) in the Genome Aggregation Database. The tyrosine at codon 169 is highly conserved but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Lassuthova P et al. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin Genet. 2011 Oct;80(4):334-45. Lupski JR et al. Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy. Genome Med. 2013 Jun 27;5(6):57.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: no PMID, 23224362, 31111683, 23806086, 23293578, 20689565, 21331778, 23281072, 26392352, 29321516, 20220177, 26794302, 34426522, 32376792, 27535533, 21291453)

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

We conducted a clinical examination of patients about toe walking. The SH3TS2:c.505T>C was detected in 4 patients. 3 patients have toe walkers in the family (2 patients have toe walking fathers, 1 has a toe walking mother). We also examined a control group of children without toe walking (100 children). In this group this variant could not be identified. Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.

SH3TC2: PS4:Supporting, BP2, BS2

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, type 4C (CMT) (MIM#601596). The mechanism of disease for mild mononeuropathy of the median nerve (MIM#613353) is unknown, but gain of function has been suggested (PMID: 20220177). (I) 0108 - This gene is associated with both recessive and dominant disease. CMT is caused by biallelic variants, while autosomal dominant mild mononeuropathy of the median nerve is rare and has been reported in one family (OMIM, PMID: 20220177). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (293 heterozygotes, 2 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has conflicting reports from likely benign to likely pathogenic in ClinVar. This variant has been reported in the compound heterozygous state in one patient with CMT (PMID: 21291453) as well as two heterozygous individuals with CMT where both individuals also harboured likely pathogenic or pathogenic variants in other genes (PMID: 26392352). This variant has also been reported in heterozygous state in a proband with a confirmed genetic diagnosis of infantile spinal muscular atrophy. The variant was inherited from the healthy father (PMID: 26794302). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant was originally reported in a family with four affected children, all showing compound heterozygosity for this variant and a nonsense variant. In a follow up study on the same family, an additional start-loss variant was identified in cis with this variant. Therefore, although this variant segregated with disease in this family, it is unknown if it contributes to the phenotype (PMID: 20220177). (I) 1007 - No published functional evidence has been identified for this variant. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign