Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV000791283 | SCV005903725 | pathogenic | Intellectual disability, autosomal dominant 6 | 2024-03-13 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.84 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.94 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000208643 /PMID: 28867141). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25533962, 28867141). Different missense changes at the same codon (p.Gly820Arg, p.Gly820Glu, p.Gly820Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000234635, VCV000521172, VCV000546296, VCV000580700 /PMID: 25356899, 28377535, 31628766 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000791283 | SCV003932141 | pathogenic | Intellectual disability, autosomal dominant 6 | 2023-02-21 | criteria provided, single submitter | clinical testing | PS3_Moderate, PM2, PM6_Strong, PP2, PP3 |
| Laboratory of Medical Genetics, |
RCV000791283 | SCV001976966 | pathogenic | Intellectual disability, autosomal dominant 6 | 2021-10-01 | criteria provided, single submitter | clinical testing | PS2, PM1, PM2, PM5, PP2, PP3 |
| Institute of Human Genetics, |
RCV000791283 | SCV001335375 | likely pathogenic | Intellectual disability, autosomal dominant 6 | 2017-04-04 | criteria provided, single submitter | clinical testing | This variant was identified as de novo (maternity and paternity confirmed). |
| Undiagnosed Diseases Network, |
RCV000791283 | SCV000930581 | likely pathogenic | Intellectual disability, autosomal dominant 6 | 2019-02-08 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000464558 | SCV000552119 | pathogenic | Intellectual disability, autosomal dominant 6; Developmental and epileptic encephalopathy, 27 | 2023-03-13 | criteria provided, single submitter | clinical testing | 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) performed at Invitae indicates that this missense variant is expected to disrupt GRIN2B protein function. This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 820 of the GRIN2B protein (p.Gly820Ala). This variant is present in population databases (rs797044849, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of epileptic encephalopathy and developmental delay (PMID: 28856709; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208643). This variant disrupts the p.Gly820 amino acid residue in GRIN2B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25356899). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000235569 | SCV000293376 | pathogenic | not provided | 2021-04-01 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate that G820A stabilizes long-lived open states leading to slow deactivation and high Ca2+ permeability (Amin et al., 2018); This variant is associated with the following publications: (PMID: 28867141, 27818011, 28135719, 28856709, 28377535, 29681796, 30217972, 28191890, 33490948, 32144935, 33176815) |
| Ambry Genetics | RCV000190648 | SCV000244088 | pathogenic | Inborn genetic diseases | 2024-11-22 | criteria provided, single submitter | clinical testing | The c.2459G>C (p.G820A) alteration is located in exon 12 (coding exon 11) of the GRIN2B gene. This alteration results from a G to C substitution at nucleotide position 2459, causing the glycine (G) at amino acid position 820 to be replaced by an alanine (A). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the results of a de novo alteration in multiple individuals with features consistent with GRIN2B-related neurodevelopmental disorder (Platzer, 2017; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
| Diagnostic Laboratory, |
RCV000235569 | SCV001963223 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000235569 | SCV001959693 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Genome Diagnostics Laboratory, |
RCV000235569 | SCV001931004 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Genome |
RCV001265246 | SCV001443360 | pathogenic | Complex neurodevelopmental disorder | 2018-10-22 | no assertion criteria provided | provider interpretation | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-10-22 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. |