Variant classification summary

NM_005896.4:c.395G>A

IDH1 · NP_005887.2:p.(Arg132His) · NM_005896.4

GRCh37: chr2:209113112 C>T · GRCh38: chr2:208248388 C>T

Gene: IDH1 Transcript: NM_005896.4

Final call

Pathogenic

PS3 strong PM1 moderate PM2 supporting PM5 moderate PP3 moderate

Variant details

Gene

IDH1

Transcript

NM_005896.4

Protein

NP_005887.2:p.(Arg132His)

gnomAD AF

9.916146585436898e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: Independent biochemical, cellular, and in-vivo studies demonstrate damaging neomorphic effects of IDH1 p.Arg132His.

2

PM1 moderate: Arg132 is a recurrent IDH1 hotspot and active-site gate-keeper residue without reported benign hotspot variation.

3

PM2 supporting: gnomAD v4.1 allele frequency is 9.91615e-06 with zero homozygotes, below the generic threshold.

4

PM5 moderate: Recurrent R132C, R132L, and R132S substitutions show the same IDH1 gain-of-function activity.

5

PP3 moderate: REVEL score 0.852 exceeds the generic moderate threshold of 0.773.

Final determination: Under the generic ACMG/AMP 2015 rules, 1 strong plus 3 moderate pathogenic criteria satisfies Pathogenic; the additional supporting PM2 criterion is consistent with that call.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no documented pathogenic alternate nucleotide change producing the same p.Arg132His substitution was available.	clinvar
PS2	Not assessed	Not assessed: a ClinVar record labels the origin de novo, but maternity, paternity, family history, and proband-level documentation are unavailable.	clinvar
PS3	Met	Met: Independent biochemical, cellular, and mouse studies show IDH1 R132H neomorphic activity, including approximately tenfold increased serum 2-hydroxyglutarate and impaired differentiation.	PMID:19935646 PMID:21446021 PMID:22763442 PMID:23393090 PMID:22343889
PS4	Not assessed	Not assessed: no exact-variant case-control relative risk or odds ratio with a confidence interval was available for comparison with the >5.0 and non-inclusive-of-1.0 requirements.
PM1	Met	Met: Arg132 is a statistically significant IDH1 hotspot and active-site gate-keeper residue, while gnomAD v4.1 frequency is 16/1,613,530 alleles.	PMID:19935646 gnomad_v4
PM2	Met	Met at supporting strength: gnomAD v4.1 AF 9.91615e-06 is below the <=0.0001 PM2 threshold, with zero homozygotes.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no affected-proband observation or parental testing establishes this variant in trans with a pathogenic variant for a recessive disorder.	clinvar
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Met	Met: R132C, R132L, and R132S are recurrent same-residue IDH1 substitutions in human gliomas with the same gain-of-function activity.	PMID:19935646
PM6	Not assessed	Not assessed: de novo origin is recorded in ClinVar, but the clinical case and basis for assuming de novo status are undocumented.	clinvar
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or family genotype-phenotype segregation data are documented.
PP2	Not assessed	Not assessed: no gene-wide evidence establishes both low benign missense variation and a common missense disease mechanism for IDH1.
PP3	Met	Met at moderate strength: missense REVEL score 0.852 exceeds the PP3 moderate threshold of 0.773.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history needed to establish a highly specific single-etiology disease presentation were not available.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel submission, so its pathogenic submissions do not qualify for PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 9.91615e-06, far below the >=0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: gnomAD v4.1 AF is 9.91615e-06, below the generic >=0.01 BS1 threshold and its maximum subpopulation AF is 3.37769e-05.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows 0 homozygotes but provides no documented healthy adult carrier observation for this criterion.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: Variant-specific assays consistently show altered IDH1 activity and 2-hydroxyglutarate production rather than no damaging effect on protein function or splicing.	PMID:19935646 PMID:21446021 PMID:22763442 PMID:23393090 PMID:22343889
BS4	Not assessed	Not assessed: no affected family members with documented negative variant testing are reported, so lack of segregation cannot be evaluated.
BP1	Not assessed	Not assessed: no systematic evidence shows that IDH1 disease is caused primarily by truncating rather than missense variants.
BP2	Not assessed	Not assessed: no phase-resolved observation shows the target variant in trans or cis with a pathogenic variant under the BP2 conditions.	clinvar
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.852 is above the BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no specific case showed this variant alongside an established alternate molecular basis for the patient's disease.
BP6	Not met	Not met: ClinVar provides no exact-variant expert-panel benign or likely benign classification to qualify for BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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