Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001390786 | SCV001592629 | pathogenic | Intellectual disability, autosomal dominant 8 | 2022-11-03 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Met641 amino acid residue in GRIN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25864721, 27164704). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1076783). This missense change has been observed in individual(s) with early onset epilepsy, visual impairment, and developmental delay (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 641 of the GRIN1 protein (p.Met641Val). For these reasons, this variant has been classified as Pathogenic. |
| 3billion | RCV001390786 | SCV003842050 | likely pathogenic | Intellectual disability, autosomal dominant 8 | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GRIN1 -related disorder (ClinVar ID: VCV001076783). Different missense changes at the same codon (p.Met641Ile, p.Met641Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000403957, VCV000828036). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Victorian Clinical Genetics Services, |
RCV001390786 | SCV005398884 | pathogenic | Intellectual disability, autosomal dominant 8 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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 variants 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 methionine to valine. (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) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These variants (p.(Met641Leu), p.(Met641Ile)) have been reported as pathogenic, and observed in at least four individuals with early onset epileptic encephalopathy or GRIN1-related disease. In three individuals, the variant was de novo (ClinVar, PMID: 25864721, PMID: 30355546). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed as de novo an individual (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |