Submissions for variant NM_018706.7(DHTKD1):c.488G>A (p.Arg163Gln)

gnomAD frequency: 0.00074  dbSNP: rs78189904

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050496	SCV001214606	uncertain significance	2-aminoadipic 2-oxoadipic aciduria	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 163 of the DHTKD1 protein (p.Arg163Gln). This variant is present in population databases (rs78189904, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Amyotrophic lateral sclerosis (PMID: 35052424). ClinVar contains an entry for this variant (Variation ID: 847040). 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 DHTKD1 protein function with a negative predictive value of 80%. 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.
GeneDx	RCV001759780	SCV002007481	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	Identified in an individual with eosinophilic esophagitis and in two unrelated individuals with amyotrophic lateral sclerosis (Sherrill et al., 2018; Osmanovic et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; In vitro functional studies showed R163Q had similar characteristics to wild type (Leandro et al., 2020); This variant is associated with the following publications: (PMID: 32633484, 35052424, 29669943)
Ambry Genetics	RCV002553729	SCV003565664	uncertain significance	Inborn genetic diseases	2021-11-24	criteria provided, single submitter	clinical testing	The c.488G>A (p.R163Q) alteration is located in exon 3 (coding exon 3) of the DHTKD1 gene. This alteration results from a G to A substitution at nucleotide position 488, causing the arginine (R) at amino acid position 163 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV001759780	SCV004126443	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing	DHTKD1: PM2, BP4
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV002221261	SCV002498598	likely pathogenic	Tip-toe gait		no assertion criteria provided	clinical testing	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.