Submissions for variant NM_005896.4(IDH1):c.394C>T (p.Arg132Cys)

gnomAD frequency: 0.00001  dbSNP: rs121913499

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000997650	SCV001153277	likely pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000997650	SCV001450436	pathogenic	not provided	2019-07-24	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000445302	SCV001478446	pathogenic	Acute myeloid leukemia	2019-03-12	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV002227473	SCV002507175	pathogenic	Enchondromatosis	2022-05-09	criteria provided, single submitter	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000997650	SCV002525674	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing	This variant results in the substitution of arginine with cysteine at position 132 within the IDH1 protein. This variant is absent from large population cohorts (Genome Aggregation Database v2.1), and has been previously reported pathogenic in numerous individuals (PMID: 23485734, PMID: 30677207, PMID: 22057236, PMID: 22057234). In addition, functional studies demonstrate that the p.R132C mutation leads to neomorphic gain of function of the IDH1 protein (PMID: 19935646).
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002291276	SCV002583825	pathogenic	Enchondromatosis; Maffucci syndrome	2022-08-11	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PP3
Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University	RCV003323531	SCV004028549	pathogenic	Glioma susceptibility 1		criteria provided, single submitter	clinical testing	The c.394C>T p.(Arg132Cys) variant in IDH1 gene was identified in the proband’s hemangioma at low read depth by whole genome sequencing. This variant was categorized in the Tier I variants by AMP Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer (Marilyn M. Li, 2017).
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458426	SCV004176913	pathogenic	Maffucci syndrome	2023-09-08	criteria provided, single submitter	clinical testing	The IDH1 c.394C>T (p.Arg132Cys) variant was identified at an allelic fraction consistent with somatic origin. It has been detected in several individuals affected with Maffucci syndrome and Ollier disease caused by somatic IDH1 c.394C>T (p.Arg132Cys) pathogenic variants (Pansuriya TC et al., PMID: 22057234; Nejo T et al., PMID: 30579273; Saiji E et al., PMID: 31240473; Amary MF et al. PMID: 22057236). This variant has been reported in the ClinVar database as pathogenic by eight submitters and as likely pathogenic by a single submitter (ClinVar ID: 375891) in both a germline and a somatic state. It also has been reported in 1150 cases in the cancer database (COSMIC ID: COSV61615256). IDH1 c.394C>T (p.Arg132Cys) is only observed on 1/151438 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within a region, amino acids 104-136, 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. Functional studies using cell lines show that this variant disrupts the resulting enzyme's ability to catalyze conversion of isocitrate to alpha-ketoglutarate (Dang L et al., PMID: 19935646). Other variants in this codon have been reported in individuals with Maffucci syndrome and Ollier disease and are considered pathogenic (Pansuriya TC et al., PMID: 22057234, ClinVar ID: 156444). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the IDH1 c.394C>T (p.Arg132Cys) variant is classified as pathogenic.
Database of Curated Mutations (DoCM)	RCV000437909	SCV000503818	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445302	SCV000503819	pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426141	SCV000503820	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436904	SCV000503821	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419656	SCV000503822	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430360	SCV000503823	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435816	SCV000503824	likely pathogenic	Adenoid cystic carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418601	SCV000503825	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429279	SCV000503826	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439965	SCV000503827	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420988	SCV000503828	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428207	SCV000503829	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438918	SCV000503830	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421691	SCV000503831	likely pathogenic	Astrocytoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434107	SCV000503832	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441917	SCV000503833	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Molecular Diagnostics Laboratory, University of Rochester Medical Center	RCV000445302	SCV002506981	pathogenic	Acute myeloid leukemia		no assertion criteria provided	curation
Sung Lab, Department of Medicine, Roswell Park Comprehensive Cancer Center	RCV000445302	SCV003932621	pathogenic	Acute myeloid leukemia	2023-06-08	no assertion criteria provided	clinical testing