ClinVar

This variant is classified as a variant of unknown significance because its contribution to progressive myoclonic epilepsy (see, e.g., EPM1A, 254800) has not been confirmed.

In a girl, born of consanguineous Iraqi parents, with progressive myoclonic epilepsy, Giddens et al. (2017) identified a heterozygous c.1047G-T transversion (c.1047G-T, NM_004767.3) in the GPR37L1 gene, resulting in a lys349-to-asn (K349N) substitution in the third intracellular loop. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was heterozygous in the unaffected parents. The variant was not found in 3,970 in-house control exomes, but was found in heterozygous state at a low frequency (0.002%) in the ExAC database. There were 5 additional deceased family members with a similar disorder, although DNA was not available. These affected individuals presented around the age of puberty with recurrent headaches, visual hallucinations, seizures, and EEG abnormalities, followed by progressive myoclonic epilepsy and cognitive decline, resulting in death in young adulthood. Two younger brothers of the proband were also homozygous for the variant: both had recurrent headaches and 1 also had visual hallucinations, suggesting that they were similarly affected. In vitro functional expression studies in HEK293 cells showed that the variant receptor had normal expression, surface trafficking, and localization, and did not alter signaling when compared to wildtype.