Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001290143.2(ADGRG1):c.-240C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,614,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
ADGRG1 (HGNC:4512): (adhesion G protein-coupled receptor G1) This gene encodes a member of the G protein-coupled receptor family and regulates brain cortical patterning. The encoded protein binds specifically to transglutaminase 2, a component of tissue and tumor stroma implicated as an inhibitor of tumor progression. Mutations in this gene are associated with a brain malformation known as bilateral frontoparietal polymicrogyria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.492
PP5
Variant 16-57651421-C-T is Pathogenic according to our data. Variant chr16-57651421-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Feb 08, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Neuberg Centre For Genomic Medicine, NCGM
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The stop gained c.286C>T(p.Arg96Ter) variant in ADGRG1 gene has been reported previously in ClinVar database as Likely pathogenic/Pathogenic (multiple submissions). The variant is reported with an allele frequency of 0.0004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. The nucleotide change c.286C>T in ADGRG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. Functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -
not provided Pathogenic:2
Jan 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change creates a premature translational stop signal (p.Arg96*) in the ADGRG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADGRG1 are known to be pathogenic (PMID: 15044805, 20929962). This variant is present in population databases (rs146278035, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with ADGRG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 158629). For these reasons, this variant has been classified as Pathogenic. -
Mar 23, 2022
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Inborn genetic diseases Pathogenic:1
Nov 17, 2015
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter