ClinVar Genomic variation as it relates to human health

Onset at age of three, younger halfsister also has toe walking, parents clinically not affected

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

The SH3TC2 c.3380G>A; p.Arg1127Gln variant (rs139192433) is reported in the literature a cohort of individuals affected with inherited peripheral neuropathy, although its clinical significance was considered uncertain (Antoniadi 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.19% (247/129184 alleles, including one homozygote) in the Genome Aggregation Database. The arginine at codon 1127 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.573). Although it population frequency is inconsistent with dominant disease, since a role in autosomal recessive disease cannot be ruled out, the clinical significance of the p.Arg1127Gln variant is uncertain at this time. References: Antoniadi et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. 2015 Sep 21;16:84.

We conducted a clinical examination of patients about toe walking. The SH3TC2:c.3380G>A was detected in 3 patients. 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.

The p.R1127Q variant (also known as c.3380G>A), located in coding exon 15 of the SH3TC2 gene, results from a G to A substitution at nucleotide position 3380. The arginine at codon 1127 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The SH3TC2 c.3380G>A variant is predicted to result in the amino acid substitution p.Arg1127Gln. This variant has been reported with uncertain significance in a cohort study of individuals with Charcot-Marie-Tooth disease (Volodarsky et al. 2021. PubMed ID: 32376792). This variant is reported in 0.19% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-148388512-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Reported in the heterozygous state in three individuals with symptoms of CMT1 and was described as being a variant of unknown significance (Antoniadi et al., 2015); Identified in patients with suspected Charcot-Marie-Tooth disease; however, no further clinical or segregation information was provided (Volodarsky et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26392352, 26872463, 27535533, 32376792)

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.