Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001000516 | SCV001157422 | uncertain significance | not specified | 2019-04-19 | criteria provided, single submitter | clinical testing | The DHTKD1 c.1364G>A; p.Arg455Gln variant (rs142068634) has been detected in at least three patients diagnosed with alpha-aminoadipic and/or alpha-ketoadipic aciduria (Hagen 2015), but no further evidence of pathogenicity has, to our knowledge, been published in the medical literature. This variant is found in the non-Finnish European population with an overall allele frequency of 0.03% (32/126094 alleles) in the Genome Aggregation Database. The arginine at position 455 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Arg455Gln variant is uncertain at this time. References: Hagen J et al. Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria. J Inherit Metab Dis. 2015 Sep;38(5):873-9. |
| Practice for Gait Abnormalities, |
RCV001353115 | SCV001548252 | uncertain significance | Tip-toe gait | 2020-10-06 | criteria provided, single submitter | 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. |
| Labcorp Genetics |
RCV001869419 | SCV002145232 | uncertain significance | 2-aminoadipic 2-oxoadipic aciduria | 2023-12-22 | 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 455 of the DHTKD1 protein (p.Arg455Gln). This variant is present in population databases (rs142068634, gnomAD 0.03%). This missense change has been observed in individuals with 2-aminoadipic 2-oxoadipic aciduria (PMID: 25860818). ClinVar contains an entry for this variant (Variation ID: 810993). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
| Ambry Genetics | RCV002549135 | SCV003710683 | uncertain significance | Inborn genetic diseases | 2021-02-25 | criteria provided, single submitter | clinical testing | The c.1364G>A (p.R455Q) alteration is located in exon 8 (coding exon 8) of the DHTKD1 gene. This alteration results from a G to A substitution at nucleotide position 1364, causing the arginine (R) at amino acid position 455 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001000516 | SCV005380495 | uncertain significance | not specified | 2024-08-20 | criteria provided, single submitter | clinical testing | Variant summary: DHTKD1 c.1364G>A (p.Arg455Gln) results in a conservative amino acid change located in the Dehydrogenase, E1 component domain (IPR001017) of 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 0.00012 in 245878 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DHTKD1 causing 2-Aminoadipic 2-Oxoadipic Aciduria, allowing no conclusion about variant significance. c.1364G>A has been reported in the literature in individuals affected with 2-Aminoadipic 2-Oxoadipic Aciduria as a compound heterozygous or heterozygous genotype (e.g. Hagen_2015). This report does not provide unequivocal conclusions about association of the variant with 2-Aminoadipic 2-Oxoadipic Aciduria. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25860818). ClinVar contains an entry for this variant (Variation ID: 810993). Based on the evidence outlined above, the variant was classified as uncertain significance. |