Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000624590 | SCV000742321 | pathogenic | Inborn genetic diseases | 2023-10-26 | criteria provided, single submitter | clinical testing | The c.616G>A (p.G206R) alteration is located in coding exon 5 of the TRMT10A gene. This alteration results from a G to A substitution at nucleotide position 616, causing the glycine (G) at amino acid position 206 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been previously reported in homozygous form in three siblings from a Jewish community in Uzbekistan. At the time of reporting, the siblings were 19 (female), 14 (male) and 13 (male) years of age. All three siblings had microcephaly, developmental delays and intellectual disability, short stature, and altered glucose metabolism including episodes of hypoglycemia, hyperinsulinemia and abnormal response to glucose. They also had a low birth weight and experienced recurrent seizures from 5 to 6 years of age with normal EEG findings. The female patient had delayed puberty and was amenorrheic at the time of reporting (Gillis, 2014). This variant has also been reported in homozygous form in an 11 year old Jewish female with diabetes, intellectual disability, developmental delay, bilateral hypoplastic kidneys, short stature, microcephaly, and dysmorphic features. This child was also noted to have IUGR during the pregnancy (Stern, 2022). This amino acid position is highly conserved in available vertebrate species. Authors performed in vitro functional studies with purified mutant p.G206R TRMT10A protein. Although binding of the mutant protein to a known tRNA substrate was similar to wild type, methylation studies showed almost complete loss of its methyltransferase activity. Gillis (2014) performed additional studies on this alteration using the yeast homolog, Trm10, and showed a significant reduction in the ability of the mutant protein to bind to the S-adenosyl methionine methyl donor. It was hypothesized that the loss of methyltransferase activity of the mutant enzyme is the result of its inability to bind to the methyl donor substrate (Gillis, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
| OMIM | RCV000144248 | SCV000189380 | pathogenic | Microcephaly, short stature, and impaired glucose metabolism 1 | 2014-09-01 | no assertion criteria provided | literature only | |
| Pediatric Genetics Clinic, |
RCV000144248 | SCV001712244 | pathogenic | Microcephaly, short stature, and impaired glucose metabolism 1 | 2021-05-13 | no assertion criteria provided | clinical testing |