Submissions for variant NM_005896.4(IDH1):c.395G>A (p.Arg132His)

gnomAD frequency: 0.00001  dbSNP: rs121913500

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000853347	SCV000996209	pathogenic	Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria	2018-11-02	criteria provided, single submitter	clinical testing	This variant has been previously reported as a mosaic change in patients with metaphyseal chondromatosis and elevated D-2-hydroxyglutaric aciduria (PMID: 24049096, 22025298). It is absent from the gnomAD population databases and thus is presumed to be rare. The c.395G>A, p.Arg132H variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. The p.Arg132H variant results in loss of its native enzymatic activity and gain of alternative enzymatic activity (producing D-2-hydroxyglutarate) (PMID 21446021). Structural studies demonstrated that when p.Arg132 is mutated to histidine (R132H), residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG (PMID 19935646). Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumors in patients with inborn errors of 2HG metabolism (PMID 18931888). Based on the available evidence, the c.395G>A, p.Arg132H variant is classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269510	SCV001449548	pathogenic	not provided	2019-10-29	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV002227447	SCV002507195	pathogenic	Enchondromatosis	2022-05-09	criteria provided, single submitter	clinical testing
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV002227447	SCV002764259	likely pathogenic	Enchondromatosis		criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV001269510	SCV004011290	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	IDH1: PS4, PM1, PM2, PP4, PS3:Supporting
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387509	SCV004099007	pathogenic	Metaphyseal chondromatosis	2023-08-02	criteria provided, single submitter	clinical testing	PS4, PM2, PM5, PM6_Strong, PP3
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001542733	SCV005438530	pathogenic	Glioma susceptibility 1	2024-12-18	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV001269510	SCV005685410	pathogenic	not provided	2024-12-30	criteria provided, single submitter	clinical testing	An IDH1 c.395G>A (p.Arg132His) variant was identified at a near heterozygous allelic fraction of 43.4%, a frequency which may be consistent with germline origin. This variant has been reported in a germline state in individuals with Ollier disease and gliomas (Kendroud S et al., Neurology, 92; Number 15_supplement April 9, 2019; Ikeda H et al., PMID: 36942363). It has also been reported in a somatic state in individuals with Ollier disease and Maffucci syndrome (Ashirov N et al., PMID: 37374260; Pansuriya TC et al., PMID: 22057234) and in numerous types of cancer in the cancer database COSMIC (Genomic mutation ID: COSV61615239). It has been reported in the ClinVar database as a germline pathogenic variant by six submitters (ClinVar Variation ID: 156444). The IDH1 c.395G>A (p.Arg132His) variant is only observed on 16/1,613,530 alleles in the general population (gnomAD v4.1.0), indicating it is not a common variant. This variant resides within a region of IDH1 that is defined as a critical functional domain (Reitman ZJ et al., PMID: 20513808). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to IDH1 function. In support of this prediction, functional studies using cell lines show that this variant alters the enzymatic properties of IDH1 and results in a gain-of-function for NADPH-dependent reduction of alpha-ketoglutarate (Dang L et al., PMID: 19935646). Other variants in the same codon, c.394C>T (p.Arg132Cys), c.394C>A (p.Arg132Ser) and c.395G>T (p.Arg132Leu) have been reported and are considered pathogenic (Saiji E et al., PMID: 31240473; Amary MF et al., PMID: 22057236; ClinVar variation ID's: 375891, 375893, 375889). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
OMIM	RCV000144504	SCV000189823	pathogenic	Glioblastoma multiforme, somatic	2014-08-21	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV001542733	SCV001760072	likely pathogenic	Glioma susceptibility 1		no assertion criteria provided	clinical testing