Variant classification summary

NM_005896.4:c.394C>A

IDH1 · NP_005887.2:p.(Arg132Ser) · NM_005896.4

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

Gene: IDH1 Transcript: NM_005896.4

Final call

Likely Pathogenic

PS3 supporting PM1 moderate PM2 supporting PP3 moderate

Variant details

Gene

IDH1

Transcript

NM_005896.4

Protein

NP_005887.2:p.(Arg132Ser)

gnomAD AF

0.0 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 supporting from variant-specific gain-of-function enzyme evidence.

2

Likely Pathogenic: PM1 moderate from the Arg132 active-site mutational hotspot.

3

Likely Pathogenic: PM2 supporting from absence in gnomAD v4.1.

4

Likely Pathogenic: PP3 moderate from REVEL 0.904 exceeding the 0.773 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, 2 moderate criteria plus 2 supporting criteria satisfy the Likely Pathogenic combination rule.

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 met	Not met: no pathogenic IDH1 p.Arg132Ser variant caused by a different nucleotide change was established in the reviewed evidence.	PMID:21760534 PMID:19935646 PMID:21912393
PS2	Not assessed	Not assessed: no proband-level parental testing, confirmed maternity and paternity, or family-history information is provided for IDH1 p.Arg132Ser.
PS3	Met	Met at supporting: recombinant IDH1 R132S showed gain-of-function NADPH-dependent alpha-ketoglutarate reduction to 2-hydroxyglutarate in a variant-specific enzyme assay.	PMID:19935646
PS4	Not assessed	Not assessed: affected-case reports exist, but no matched control counts were provided, so the required OR >5.0 and 95% CI excluding 1.0 cannot be calculated.	PMID:21912393 PMID:21760534 gnomad_v4
PM1	Met	Met: Arg132 is an IDH1 active-site hotspot, and the variant lies in a statistically significant hotspot with gnomAD allele count 0.	hotspots PMID:19935646 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: gnomAD v4.1 observed 0/1,613,196 alleles (AF 0), below the PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no recessive disorder, affected germline proband, pathogenic partner, or parent/offspring phasing demonstrates IDH1 p.Arg132Ser in trans.
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	Not assessed	Not assessed: other Arg132 substitutions are reported, but no cited record establishes a different Arg132 missense variant as pathogenic under the generic rule.	PMID:19935646 PMID:21326614 PMID:21760534 PMID:23630074
PM6	Not assessed	Not assessed: no presumed de novo germline occurrence is documented, and parental maternity or paternity information is unavailable for this variant.
PP1	Not assessed	Not assessed: zero affected relatives, informative meioses, or variant-positive familial segregation observations are reported for IDH1 p.Arg132Ser.
PP2	Not assessed	Not assessed: gene-level benign missense rate and a qualifying common missense disease mechanism are not established by the available evidence.
PP3	Met	Met at moderate strength: missense REVEL score 0.904 exceeds the PP3 moderate threshold of 0.773.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history detail is available to establish a highly specific phenotype for a single genetic etiology.
PP5	Not met	Not met: ClinVar has only a single-submitter Pathogenic classification, with zero expert-panel submissions, so the exact-variant PP5 requirement is not satisfied.	clinvar
BA1	Not met	Not met: gnomAD v4.1 observed 0/1,613,196 alleles (AF 0), below the generic BA1 threshold of 5%.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 observed AF 0 from 0/1,613,196 alleles, below the generic BS1 default of 1%.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no healthy adult carrier is reported, and gnomAD shows 0 observed alleles and 0 homozygotes.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: IDH1 R132S showed gain-of-function 2-hydroxyglutarate production, not absence of a damaging effect on protein function or splicing.	PMID:19935646
BS4	Not assessed	Not assessed: no affected relatives with documented negative variant testing are reported, so lack of segregation cannot be evaluated.
BP1	Not assessed	Not assessed: the available evidence does not show that IDH1 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no fully penetrant dominant disorder or validated evidence places IDH1 p.Arg132Ser in trans or cis with a pathogenic variant.
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 0.904 is above the BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: JAK2V617F co-occurrence is reported for the IDH-mutated cohort, but not definitively for the exact R132S case or as its alternate disease basis.	PMID:21912393
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; the available ClinVar submission is single-submitter Pathogenic.	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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