Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000482632 | SCV000570729 | uncertain significance | not specified | 2016-06-20 | criteria provided, single submitter | clinical testing | The c.874_875delGAinsTT variant results in the deletion of two nucleotides and the insertion of two incorrect nucleotides, causing a substitution of Leucine for Glutamic acid at codon 292, denoted as p.Glu292Leu. The c.874_875delGAinsTT 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. This is variant results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, some splice predictor models indicate that this sequence change may strengthen a cryptic splice acceptor site downstream of the natural splice acceptor site of intron 9, which may result in abnormal gene splicing. We interpret c.874_875delGAinsTT as a variant of uncertain significance. |
Clinical Genomics Laboratory, |
RCV004555865 | SCV005045059 | uncertain significance | Classic homocystinuria | 2023-11-14 | criteria provided, single submitter | clinical testing | The CBS c.874_875delinsTT (p.Glu292Leu) variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on CBS function. This variant has been reported in the ClinVar database as a variant of uncertain significance by one submitter (ClinVar Variation ID: 421504). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. |