Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV003327627 | SCV004034170 | pathogenic | Autosomal recessive spinocerebellar ataxia 18 | 2023-08-24 | criteria provided, single submitter | research | A homozygous deletion of exon 1 in GRID2 (NM_001510.4) was identified by exome sequencing in 1 individual with spinocerebellar ataxia ([GRCh 38] chr4:92303869_92304842x0). These breakpoints have been estimated by exome sequencing only and therefore may not reflect the true breakpoints. Inheritance information is unavailable. The patient phenotype is nonspecific, but is consistent with cases described in the literature and/or published databases with overlapping variants. This intragenic variant is predicted to cause loss of the methionine initiation codon. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of GRID2 is an established disease mechanism in autosomal recessive spinocerebellar ataxia. More than 30 affected individuals have been reported with the phenotype and biallelic variants in GRID2 (PMID: 35769960) and a knockout GRID2 mouse model showed cerebellar ataxia (PMID: 7736576, 9628817). A slightly larger deletion has been identified in 0.04% (1/2416) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; Structural variant: DEL_4_47837). Although a deletion overlapping the region of this CNV has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spinocerebellar ataxia. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1: 0 points, 2: 0.9 points, 3: 0 points, 4-5: 0.15 points; Total: 1.05 points; Riggs 2020 (PMID: 31690835). |