Submissions for variant NM_007118.4(TRIO):c.4283G>A (p.Arg1428Gln)

dbSNP: rs879255626

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000239597	SCV001432986	pathogenic	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2020-09-10	criteria provided, single submitter	curation	This variant is interpreted as pathogenic for Intellectual developmental disorder, autosomal dominant 44, with microcephaly. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1); Well-established functional studies show a deleterious effect (PS3 downgraded to moderate).
Baylor Genetics	RCV000239597	SCV001527543	pathogenic	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2018-05-30	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in one patient with global developmental delay [PMID 27418539]
GeneDx	RCV001545744	SCV001765132	pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (reduced ability to activate Rac1 as compared to wild-type) (Pengelly et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28928363, 24782526, 27418539, 32109419, 31785789, 33038108, 35599849, 34697084, 36717740)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000239597	SCV001950016	pathogenic	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2021-10-06	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS4_MOD, PS3_SUP, PM1_SUP, PM2_SUP, PP2, PP3
3billion	RCV000239597	SCV002521484	pathogenic	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:32109419). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000253084). The variant has been previously reported as de novo in a similarly affected individual (PMID: 32109419). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000239597	SCV002581550	pathogenic	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2022-04-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004547623	SCV004120094	pathogenic	TRIO-related disorder	2023-04-27	criteria provided, single submitter	clinical testing	The TRIO c.4283G>A variant is predicted to result in the amino acid substitution p.Arg1428Gln. This variant has been reported to occur de novo in individuals with TRIO-related autosomal dominant intellectual developmental disorder (Patient 4; Pengelly et al. 2016. PubMed ID: 27418539; Barbosa et al. 2020. PubMed ID: 32109419). Functional studies suggest this variant impairs Trio-mediated Rac1 activation (Pengelly et al. 2016. PubMed ID: 27418539). This variant occurs in the Dbl homology domain (DH1), which is considered a mutation hotspot in the TRIO protein (Sadybekov. 2017. PubMed ID: 28928363). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001545744	SCV005196875	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV000239597	SCV005725465	likely pathogenic	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2025-02-14	criteria provided, single submitter	clinical testing	ACMG: PS3_Supporting, PS4_Moderate, PM1_Supporting, PM2_Supporting, PM6, PP2, PP3
OMIM	RCV000239597	SCV000297882	pathogenic	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2020-03-31	no assertion criteria provided	literature only
GeneReviews	RCV000239597	SCV000679646	not provided	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome		no assertion provided	literature only
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000239597	SCV000803691	pathogenic	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2017-09-28	no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV000239597	SCV005091358	likely pathogenic	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team