ClinVar Genomic variation as it relates to human health

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 sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1062 of the PRX protein (p.Lys1062Asn). This variant is present in population databases (rs139188673, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of PRX-related conditions (PMID: 31523542, 32376792). ClinVar contains an entry for this variant (Variation ID: 245910). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRX protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The PRX c.3186G>T; p.Lys1062Asn variant (rs139188673) is reported in the literature in multiple individuals with suspected CMT (Datta 2019, Volodarsky 2021). This variant is also reported in ClinVar (Variation ID: 245910). This variant is found in the non-Finnish European population with an allele frequency of 0.16% (204/129,096 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.101). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Datta S et al. A Case Report on Charcot-Marie-Tooth Disease with a Novel Periaxin Gene Mutation. Cureus. 2019 Jul 9;11(7):e5111. PMID: 31523542. Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792.

The p.K1062N variant (also known as c.3186G>T), located in coding exon 4 of the PRX gene, results from a G to T substitution at nucleotide position 3186. The lysine at codon 1062 is replaced by asparagine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

We examined a family - mother, father and son. Son is toe-walker and mother had toe-walking in childhood too. They both had this variant ( Lys1062Asn in PRX) . Father doesn't have this variant and he is not toe-walker. 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.

Variant summary: PRX c.3186G>T (p.Lys1062Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 251366 control chromosomes. c.3186G>T has been reported in the literature in individuals affected with PRX-Related Disorders (example: Datta_C2019, Malatesta_2020, Volodarsky_2021). These report(s) do not provide unequivocal conclusions about association of the variant with PRX-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31523542, 32376792, 32453099). ClinVar contains an entry for this variant (Variation ID: 245910). Based on the evidence outlined above, the variant was classified as uncertain significance.

Identified in the heterozygous state in an individual with a mild clinical form of CMT4F (PMID: 31523542); Identified in an individual receiving paclitaxel treatment who was reported to have low or no neuropathy (PMID: 27582484); 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: 32085570, 32376792, 35509735, 37091313, 27582484, 31523542)

BP4