NM_005896.3:c.394C>A

IDH1 · NP_005887.2:p.(Arg132Ser) · NM_005896.3

GRCh37: chr2:209113113 G>T · GRCh38: chr2:208248389 G>T

Gene: IDH1 Transcript: NM_005896.3

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 moderate PM5 moderate PP3 supporting

Variant details

Gene

IDH1

Transcript

NM_005896.3

Protein

NP_005887.2:p.(Arg132Ser)

gnomAD AF

0.0 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

IDH1 c.394C>A (p.Arg132Ser) is absent from population databases (gnomAD v4.1: 0/1,613,196 alleles).

The variant alters the critical active-site residue Arg132 of IDH1, a well-established mutational hotspot and functional domain essential for substrate binding and catalysis.

Different missense changes at the same residue (p.Arg132His, p.Arg132Cys) are established pathogenic variants, satisfying PM5.

Functional studies directly testing the R132S mutant protein demonstrate neomorphic gain-of-function activity: NADPH-dependent reduction of α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate.

Multiple in silico tools support a deleterious effect, including a REVEL score of 0.904 and a SpliceAI max delta of 0.61.

ClinVar reports this variant as Pathogenic (VariationID 375893) based on a single clinical laboratory submission with criteria provided (1-star). This does not reach the 3-star expert panel threshold required for PP5.

The variant has been reported in somatic cancers (COSMIC: n=217), primary myelofibrosis (3/301 patients; PMID:21912393), and a case of adult medulloblastoma (PMID:24616312), consistent with oncogenicity but not meeting germline PS4 thresholds.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (c.394C>A, p.Arg132Ser). It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 framework assessment indicates 'apply_generic_pvs1_framework: false' and variant_bucket is 'other'.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at this codon producing the same amino acid substitution (p.Arg132Ser) that has been previously classified as pathogenic. PS1 requires a different nucleotide change resulting in the identical amino acid change with an established pathogenic classification, which is not present in the available data.
PS2	Not met	No de novo data available for this variant. No report of de novo occurrence with confirmed maternity and paternity was found in ClinVar, the literature, or any other source.
PS3	Met	The IDH1 R132S variant was directly tested in recombinant protein functional assays. Dang et al. (2009) generated purified recombinant R132S mutant IDH1 protein and demonstrated that R132S, like other R132 mutations, results in gain-of-function NADPH-dependent reduction of α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate. The functional effect is unequivocal: the mutation alters enzymatic activity from oxidative decarboxylation of isocitrate to reductive production of 2-HG. A single study with direct variant-specific testing supports moderate-strength PS3.	PMID:19935646
PS4	Not met	No case-control comparison data available to demonstrate statistically significant increased prevalence of this variant in affected individuals versus controls. The variant has been observed in somatic cancers (COSMIC: 217 times) and in clinical cohorts (3/301 PMF patients in PMID:21912393, 1 case of adult medulloblastoma in PMID:24616312), but these are somatic observations and do not constitute germline case-control evidence for PS4.	PMID:21912393 PMID:24616312
PS5	Not met	No segregation data available for this variant. No family studies or co-segregation analysis were identified in ClinVar or the reviewed literature.
PM1	Met	The variant alters Arg132, the critical active-site residue of IDH1 responsible for isocitrate substrate binding and catalysis. This residue is located in the enzyme's catalytic domain and is a statistically significant mutational hotspot (cancerhotspots.org). All known oncogenic IDH1 mutations occur at this residue. The Arg132 position forms hydrogen bonds with the α- and β-carboxyl groups of isocitrate and is essential for normal enzymatic function.	PMID:19935646 PMID:23630074
PM2	Met	This variant is completely absent from population databases. gnomAD v4.1 reports 0 alleles in 1,613,196 alleles across all populations (AF=0.000%). gnomAD v2.1 and gnomAD-Canada v1.0 also report complete absence. The allele frequency is well below the 0.1% threshold for PM2 under generic ACMG rules.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Met	A different missense change at the same amino acid residue (p.Arg132) has been established as pathogenic. IDH1 p.Arg132His (R132H) is the most common and well-characterized pathogenic IDH1 variant in gliomas and other cancers. p.Arg132Cys (R132C) is also established as pathogenic. Both are listed as pathogenic in ClinVar and extensively characterized in the literature. The current variant, p.Arg132Ser, is a different amino acid change at the same residue.	clinvar PMID:19935646 PMID:23630074
PM6	Not met	No de novo data available. PM6 requires confirmed de novo occurrence with both maternity and paternity confirmed. No such evidence was identified in ClinVar or the reviewed literature.
PP1	Not met	No co-segregation data available. No family studies demonstrating co-segregation of this variant with disease were identified.
PP2	Not assessed	Insufficient data to assess the missense constraint profile of IDH1 for germline disease. HCI prior score is not available for IDH1. While IDH1 is known for recurrent somatic missense mutations in cancer, the gene-level missense constraint metrics for germline disease are not established in the available data.
PP3	Met	Multiple in silico tools support a deleterious effect. REVEL score is 0.904 (strongly pathogenic prediction). SpliceAI predicts a possible splice impact with a maximum delta score of 0.61 (donor gain delta = 0.61, donor loss delta = 0.48). BayesDel score is 0.419 (moderate). The high REVEL score and moderate SpliceAI signal together provide supporting evidence for a deleterious effect.	revel spliceai bayesdel
PP4	Not assessed	No specific patient phenotype or clinical information was provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Without phenotype data, PP4 cannot be assessed.
PP5	Not met	ClinVar reports this variant as Pathogenic with review status 'criteria provided, single submitter' (1 star). Under the current PP5 rule, only 3-star expert panel ClinVar submissions qualify for PP5 at supporting strength. The available ClinVar submission is from a single clinical laboratory (CeGaT Center for Human Genetics Tuebingen), not an expert panel. At 1-star review status, PP5 is not met.	clinvar
BA1	Not met	This variant is absent from gnomAD v4.1 (0/1,613,196 alleles, AF=0.000%), well below the BA1 threshold of >1% allele frequency. It is not a common polymorphism.	gnomad_v4 gnomad_v2
BS1	Not met	This variant is absent from gnomAD v4.1 (0/1,613,196 alleles, AF=0.000%), well below the BS1 threshold of >0.3% allele frequency. It is not observed at a frequency consistent with a benign variant.	gnomad_v4 gnomad_v2
BS2	Not met	This variant has not been observed in healthy adult individuals. It is completely absent from gnomAD population databases. No evidence of observation in healthy controls exists.	gnomad_v4 gnomad_v2
BS3	Not met	Well-established functional studies demonstrate a damaging gain-of-function effect, not a benign effect. Dang et al. (2009) showed that R132S mutant IDH1 produces the oncometabolite (R)-2-hydroxyglutarate through neomorphic enzymatic activity. This functional evidence supports pathogenicity, not benign impact.	PMID:19935646
BS4	Not met	No segregation data available. BS4 requires lack of segregation in affected family members, which cannot be assessed without family studies.
BP1	Not met	IDH1 disease mechanism in cancer is primarily gain-of-function via missense mutations at Arg132. The gene is not characterized by a primary truncating variant disease mechanism. BP1 does not apply because IDH1 pathogenicity is mediated by missense changes at a critical functional residue, not by loss-of-function through truncation.	PMID:19935646
BP2	Not met	No data available regarding observation of this variant in trans with a pathogenic variant. No compound heterozygosity data exists for this variant.
BP4	Not met	Multiple in silico tools predict a deleterious effect, not a benign effect. REVEL score is 0.904 (strongly pathogenic). SpliceAI delta score is 0.61 (possible splice impact). These computational predictions support pathogenicity, not benign impact.	revel spliceai bayesdel
BP5	Not met	ClinVar classifies this variant as Pathogenic, not benign. The single submission from a clinical laboratory reports the variant as Pathogenic. No reputable source classifies this variant as benign.	clinvar
BP6	Not met	ClinVar classifies this variant as Pathogenic, not benign. No reputable source reports this variant as benign. The single ClinVar submission reports Pathogenic with review status 'criteria provided, single submitter.'	clinvar
BP7	N/A	This is a missense variant (p.Arg132Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	This is a substitution variant, not an in-frame deletion or insertion. BP3 applies to in-frame indels in repeat regions.
PM3	N/A	No evidence of recessive inheritance for IDH1-associated disease. PM3 requires observation in trans with a pathogenic variant for recessive disorders.
PM4	N/A	This is a substitution variant, not an in-frame deletion or insertion. PM4 applies only to protein length-altering variants.

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