Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001067257 | SCV001232307 | uncertain significance | Intellectual disability, autosomal dominant 8 | 2023-02-08 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 141 of the GRIN1 protein (p.Val141Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GRIN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 860867). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GRIN1 protein function. 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. |
| Laboratory of Medical Genetics, |
RCV001067257 | SCV002760093 | likely pathogenic | Intellectual disability, autosomal dominant 8 | 2022-11-29 | criteria provided, single submitter | research | |
| Victorian Clinical Genetics Services, |
RCV001067257 | SCV003921962 | likely pathogenic | Intellectual disability, autosomal dominant 8 | 2020-11-05 | criteria provided, single submitter | clinical testing | 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with both autosomal dominant and recessive neurodevelopmental disorder with or without hyperkinetic movements and seizures (MIM#614254, MIM#617820). (I) 0108 - This gene is associated with both recessive and dominant disease. Missense variants and variants predicted to result in a premature termination codon located in the N-terminal domain, tend to be associated to recessive disease. Missense mutations with both gain of function and dominant negative consequences on protein function are associated to dominant disease, and tend to be found in C-terminal domains (PMID: 27164704, PMID: 29365063, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional hinge region of the N-terminal domain. Seven alternative missense changes at this residue have been functionally proven to have both loss and gain of function effects in channel activity (PMID: 23454977). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |