Submissions for variant NM_201525.4(ADGRG1):c.1442T>C (p.Leu481Pro)

dbSNP: rs587783653

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146039	SCV000193194	pathogenic	Bilateral frontoparietal polymicrogyria	2013-02-08	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000146039	SCV002507010	uncertain significance	Bilateral frontoparietal polymicrogyria	2022-05-04	criteria provided, single submitter	curation	The homozygous p.Leu487Pro variant in ADGRG1 (also known as GPR56) was identified by our study in 2 siblings with bilateral frontoparietal polymicrogyria. The variant has not been previously reported in individuals with bilateral frontoparietal polymicrogyria and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 158619) as pathogenic by Genetic Services Laboratory, University of Chicago. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in at least 1 affected homozygotes, and in an individual with bilateral frontoparietal polymicrogyria, increases the likelihood that the variant is pathogenic. In summary, the clinical significance of the p.Leu487Pro variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003727620	SCV004539120	likely pathogenic	not provided	2023-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 487 of the ADGRG1 protein (p.Leu487Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with frontoparietal polymicrogyria (PMID: 28397838, 29707406). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158619). 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 ADGRG1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.