Submissions for variant NM_201525.4(ADGRG1):c.1675C>T (p.Arg559Trp)

gnomAD frequency: 0.00003  dbSNP: rs121908464

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427813	SCV000520869	likely pathogenic	not provided	2016-09-27	criteria provided, single submitter	clinical testing	The R565W variant in the GPR56 gene has been reported previously in the homozygous state in multiple children affected with bilateral frontoparietal polymicrogyria (Piao et al., 2004; Piao et al., 2005). Functional studies show that cells transfected with R565W demonstrate a lack of surface expression (Ke et al., 2008; Luo et al., 2014). The R565W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R565W variant is a non-conservative amino acid substitution, which occurs at a position that is not conserved. Therefore, the R565W variant is a strong candidate for a pathogenic variant.
CeGaT Center for Human Genetics Tuebingen	RCV000427813	SCV001249678	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV000427813	SCV001397070	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 565 of the ADGRG1 protein (p.Arg565Trp). This variant is present in population databases (rs121908464, gnomAD 0.008%). This missense change has been observed in individuals with bilateral frontoparietal polymicrogyria (PMID: 15044805, 19016831). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5831). 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 ADGRG1 protein function. Experimental studies have shown that this missense change affects ADGRG1 function (PMID: 21349848, 24949629, 28424266). For these reasons, this variant has been classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000006187	SCV002072859	pathogenic	Bilateral frontoparietal polymicrogyria		criteria provided, single submitter	clinical testing	The missense variant p.R565W in ADGRG1 (NM_005682.7) has been previously reported in mutliple affected indviduals (Chiang NY et al).Functional studies have shown a damaging effect (Luo R et al). The variant has been submitted to ClinVar as Pathogenic. The p.R565W variant is observed in 1/34,456 (0.0029%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R565W missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1693 in ADGRG1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000006187	SCV000026369	pathogenic	Bilateral frontoparietal polymicrogyria	2011-07-01	no assertion criteria provided	literature only