ClinVar Genomic variation as it relates to human health

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 70 of the TTR protein (p.Ser70Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 31371117). ClinVar contains an entry for this variant (Variation ID: 808383). 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 expected to disrupt TTR protein function. This variant disrupts the p.Ser70 amino acid residue in TTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1335038, 2363717, 22745357, 22928869, 23713495, 24053266, 27273296). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 p.S70N variant (also known as c.209G>A), located in coding exon 3 of the TTR gene, results from a G to A substitution at nucleotide position 209. The serine at codon 70 is replaced by asparagine, an amino acid with highly similar properties. This alteration, which is also known as p.S50N, has been reported in an individual with hypertrophic cardiomyopathy (HCM), but it is also present in general population databases (Lahuerta Pueyo C et al. Eur. J. Hum. Genet., 2019 May;27:783-791; Maurizi N et al. Int. J. Cardiol., 2020 02;300:191-195). This amino acid position is not well 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.

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.

Reported previously as a likely pathogenic heterozygous variant in patients with polyneuropathy and/or cardiomyopathy (PMID: 34658264); Reported previously in a patient with atrial fibrillation; however, no further clinical information was provided (PMID: 31371117); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30683924, 31567998, 34658264, 31371117)