Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000427422 | SCV000534400 | likely pathogenic | not provided | 2016-12-20 | criteria provided, single submitter | clinical testing | The L2431P variant in the MTOR gene has not been reported previously as a germline pathogenic variant, nor as a benign variant, to our knowledge. The L2431P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L2431P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The L2431P variant is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded. |
| Clinical Genomics Laboratory, |
RCV001253755 | SCV001427215 | likely pathogenic | Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome | 2019-12-23 | no assertion criteria provided | clinical testing | The p.Leu2431Pro variant in the MTOR gene was identified de novo in this individual, and has been previously reported de novo in 1 individual with developmental delay, hypotonia, macrocephaly and seizures (GeneDx pers. comm., December 13, 2019). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The MTOR gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that the p.Leu2431Pro variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Leu2431Pro variant as likely pathogenic for SmithKingsmore syndrome in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2; PM2; PP2; PP3] |