Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute of Human Genetics, |
RCV000767486 | SCV000898101 | pathogenic | Tubulinopathy | 2018-07-01 | criteria provided, single submitter | literature only | A variant that is classified as pathogenic has been identified in the TUBA1A gene in a 30 months old born individual of male sex. The c.352G>C, p.(Val118Leu) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Romaniello et al. Eur Radiol, 2017 PMID: 28677066. HPO-standardized clinical features were: Agenesis of the corpus callosum (HP:0001274); Cortical gyral simplification (HP:0009879); Dysgenesis of the cerebellar vermis (HP:0002195); Brainstem dysplasia (HP:0002508); Dilated fourth ventricle (HP:0002198); Abnormality of the internal capsule (HP:0012502); Congenital microcephaly (HP:0011451); Spasticity (HP:0001257); Focal seizures (HP:0007359) |
| Rady Children's Institute for Genomic Medicine, |
RCV003336173 | SCV004046232 | pathogenic | TUBA1A-associated tubulinopathy | criteria provided, single submitter | clinical testing | This variant has been previously reported as a de novo change in a 3 years-old boy with delayed development, spastic tetraparesis, severe ID, congenital microcephaly and focal seizures (PMID: 28677066). A different missense variant affecting the same amino acid residue (c.352G>A, p.Val118Met) has been previously reported in a 4 year-old individual with astigmatism, early tooth eruption, premature adult teeth, brain malformation, developmental delay, spasticity, hyperreflexia and wide based gait (PMID: 25326637). The TUBA1A gene is constrained against variation (Z-score= 5.58 and pLI = 0.97), and missense variants have been reported in individuals with TUBA1A-associated tubulinopathy (HGMD, ClinVar database; PMID: 24860126, 28677066, 25326637). The c.352G>C variant is absent from the gnomAD population database and thus is presumed to be rare. The c.352G>C variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.352G>C variant is classified as Pathogenic. |