Variant classification summary

NM_005896.4:c.394C>G

IDH1 · NP_005887.2:p.(Arg132Gly) · NM_005896.4

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

Gene: IDH1 Transcript: NM_005896.4

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 supporting PP3 moderate

Variant details

Gene

IDH1

Transcript

NM_005896.4

Protein

NP_005887.2:p.(Arg132Gly)

gnomAD AF

0.0 (v4.1)

ClinVar

Tier I - Strong

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 moderate is supported by IDH1-dependent 2-hydroxyglutarate production in endogenous R132G cells.

2

Likely Pathogenic: PM1 moderate is supported by the R132 active-site hotspot and absence of benign population variation.

3

Likely Pathogenic: PM2 supporting is met because the variant is absent from gnomAD v4.1 (0/1,613,198 alleles).

4

Likely Pathogenic: PP3 moderate is met because REVEL is 0.893, above the 0.773 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, three moderate pathogenic criteria plus one supporting pathogenic criterion 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 assessed	Not assessed: R132G is reported in cancer studies, but no supplied source establishes a previously observed R132G variant as ACMG/AMP pathogenic.	PMID:23264629 PMID:19935646 clinvar
PS2	Not assessed	Not assessed: no germline proband-parent testing or confirmed maternity and paternity establishes de novo occurrence in an affected patient.
PS3	Met	Met at moderate strength: endogenous monoallelic IDH1 R132G cells produced measurable 2HG, and IDH1 knockdown reduced accumulation, supporting altered pathogenic enzyme activity.	PMID:23264629 PMID:19935646
PS4	Not assessed	Not assessed: no exact-variant case-control counts or valid OR with 95% CI are available for comparison with the PS4 threshold OR >5.0 and CI excluding 1.0.	PMID:29860938 PMID:23264629 gnomad_v2 gnomad_v4
PM1	Met	Met: IDH1 R132 is an active-site residue and statistically significant hotspot, with 0/1,613,198 gnomAD v4.1 alleles observed.	PMID:19935646 PMID:29670690 hotspots gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant is absent, 0/1,613,198 alleles, below the PM2 supporting threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, second pathogenic variant, parental testing, or phase result establishes a pathogenic variant 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: alternate R132 substitutions are reported, but none is established in the supplied evidence as a pathogenic comparator for PM5.	PMID:19935646 cosmic oncokb clinvar
PM6	Not assessed	Not assessed: no affected germline proband or parental testing supports an assumed de novo occurrence without confirmed maternity and paternity.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are documented to evaluate co-segregation with disease.
PP2	Not assessed	Not assessed: no supplied evidence establishes both low benign missense variation and a common germline missense disease mechanism for IDH1.
PP3	Met	Met at moderate strength: missense REVEL score 0.893 exceeds the PP3 threshold of 0.773.	revel
PP4	Not assessed	Not assessed: no case-level phenotype or family history is available to determine whether it is highly specific for a single-genetic-etiology disease.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic assertion; its record is single-submitter somatic Oncogenic/Tier I - Strong.	clinvar
BA1	Not met	Not met: observed allele frequency is 0/1,613,198 in gnomAD v4.1, far below the generic BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: observed allele frequency is 0/1,613,198 in gnomAD v4.1 and therefore does not reach the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying healthy-adult carrier or homozygote observation was provided for the BS2 requirement.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no well-established assay in the reviewed evidence demonstrates that IDH1 R132G has no damaging effect on protein function or splicing.	PMID:23264629 PMID:19935646 PMID:29670690 PMID:29860938
BS4	Not assessed	Not assessed: no affected relatives with genotype and phenotype data are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the supplied evidence does not establish that IDH1 disease is primarily caused by truncating variants.
BP2	Not assessed	Not assessed: no documented pathogenic variant in trans for a fully penetrant dominant disorder or in cis in any inheritance pattern.
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 0.893 is above the BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: the available records do not document an individual carrying exact R132G who has an alternate molecular basis for disease.	PMID:23264629 PMID:29860938
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign assertion and instead records single-submitter somatic Oncogenic/Tier I - Strong.	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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