ClinVar Genomic variation as it relates to human health

This study shows that diverse genetic causes underlie CVI.

This variant was identified as de novo (maternity and paternity confirmed).

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28867141, 34212862, 34490615, 34673242, 26350515, 27818011, 28377535, 30842224, 31785789, 33860439, 34302356, 35240744, 35238837, 27839871)

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 689 of the GRIN2B protein (p.Gly689Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GRIN2B-related conditions (PMID: 28377535, 30842224, 34212862). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224818). 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 GRIN2B protein function. Experimental studies have shown that this missense change affects GRIN2B function (PMID: 34212862). For these reasons, this variant has been classified as Pathogenic.

PS3: In vitro functional studies showed this variant impacts protein function (PMID: 34212862). PS4 (applied as moderate) reported in various publications. PM1: Located in a mutational hot spot and/or critical and well-established functional domain (PMID: 28377535). PM2: Absent in the population databases. PM6: De novo without the confirmation of paternity and maternity PP2: GRIN2b has a low rate of benign missense variation (Z score: 7.34) PP3: In silico scores predict the variant to be damaging to the protein function. PP5: Reported as pathogenic variant in ClinVar.

The p.Gly689Ser variant in GRIN2B has been reported as a de novo variant in 8 individuals in the literature (Bosch 2016 PMID: 26350515, Platzer 2017 PMID: 28377535, Iwama 2019 PMID: 30842224, Kwok 2020 PMID: 33229608, Kellner 2021 PMID: 34212862) in association with complex neurodevelopmental disorder (intellectual disability, autosomal dominant 6, with or without epilepsy). The variant was absent from large population studies (gnomAD). This variant has also been reported in ClinVar as de novo by multiple submitters (Variation ID: 224818). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function by decreasing glutamate potency and producing a dominant negative effect on wildtype subunits (Kellner 2021 PMID: 34212862). This variant lies in the S2 ligand-binding domain, and pathogenic missense variants associated with disease cluster in the S1 and S2 ligand-binding domains (Platzer 2017 PMID: 28377535). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder. ACMG/AMP Criteria applied: PS4, PM6_VS, PM1, PS3_Supporting, PP3, PM2_Supporting.

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-02-17 and interpreted as Likely Pathogenic. Variant was initially reported on 2015-12-21 by GTR ID of laboratory name 283396. The reporting laboratory might also submit to ClinVar.