Variant classification summary

NM_001111067.4:c.617G>A

ACVR1 · NP_001104537.1:p.(Arg206His) · NM_001111067.4

GRCh37: chr2:158630626 C>T · GRCh38: chr2:157774114 C>T

Gene: ACVR1 Transcript: NM_001111067.4

Final call

Pathogenic

PS1 strong PS3 moderate PM2 supporting PM6 moderate PP3 strong

Variant details

Gene

ACVR1

Transcript

NM_001111067.4

Protein

NP_001104537.1:p.(Arg206His)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS1 strong: exact ACVR1 p.Arg206His is repeatedly reported as the recurrent FOP mutation.

2

PS3 moderate: independent assays show weakened FKBP12 inhibition and increased BMP signaling for R206H.

3

PM2 supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets.

4

PM6 moderate: the variant was absent from both parents of an affected proband without documented parentage confirmation.

5

PP3 strong: REVEL 0.948 exceeds the generic strong threshold of 0.932.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS1 and PP3) satisfy the 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	Met	Met, strong: the exact ACVR1 p.Arg206His substitution is repeatedly reported as the recurrent disease-causing FOP mutation.	PMID:22977237 PMID:24705252
PS2	Not met	Not met: the variant was absent from both parents, but confirmation of maternity and paternity was not documented.	PMID:17077940
PS3	Met	Met at moderate strength: three independent assay systems showed weakened FKBP12 inhibition and increased BMP-pathway signaling for exact ACVR1 R206H.	PMID:21525719 PMID:22977237 PMID:24705252
PS4	Not assessed	Not assessed: affected-case observations lack verified control counts, so no OR or 95% CI can be calculated against the >5.0 and 1.0 requirements.	PMID:24705252 PMID:22977237
PM1	Not assessed	Not assessed: p.Arg206His lies in the GS-rich domain, but no evidence establishes absence of benign variation in that domain.	PMID:24705252 hotspots
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, satisfying the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the reported ACVR1 disorder is autosomal dominant, and the variant was a single heterozygous change rather than a recessive trans finding.	PMID:17077940
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: no different pathogenic missense substitution at ACVR1 residue 206 was identified in the available comparator evidence.	pm5_candidates
PM6	Met	Met: the affected proband carried c.617G>A while both parents and a brother were wild type, without documented parentage confirmation.	PMID:17077940
PP1	Not assessed	Not assessed: no multiple affected family members with documented c.617G>A co-segregation were reported.
PP2	Not assessed	Not assessed: ACVR1 missense disease mechanism is supported, but no gene-level benign-missense rate is available.	PMID:22977237
PP3	Met	Met strong: missense REVEL score 0.948 exceeds the PP3 strong threshold of 0.932.	revel
PP4	Not assessed	Not assessed: patient-level phenotype and family history needed to judge highly specific FOP features are absent.
PP5	Not met	Not met: exact-variant ClinVar has 0 expert-panel submissions, and the pathogenic published evidence is available for independent evaluation.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF approaching the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no observed allele, so filtering AF is not greater than the disorder's expected frequency or the 1% default.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no supplied evidence observes the variant in a healthy adult as a heterozygote, homozygote, or hemizygote.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: available studies show reduced FKBP12 binding and increased BMP signaling, not a validated absence of damaging effect.	PMID:21525719 PMID:22977237 PMID:24705252
BS4	Not assessed	Not assessed: the tested noncarriers were unaffected relatives, not affected family members demonstrating lack of segregation.
BP1	Not met	Not met: ACVR1 disease evidence centers on activating missense variation, not primarily truncating variants.	PMID:22977237
BP2	Not assessed	Not assessed: the proband's variant was de novo and heterozygous, but no pathogenic variant in cis or trans was documented for comparison.	PMID:17077940
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 0.948 is above the strongest BP4 benign threshold of <= 0.016.	revel
BP5	Not met	Not met: no alternate molecular diagnosis explaining the case is documented alongside the variant.
BP6	Not met	Not met: no exact-variant reputable benign assertion is documented, and ClinVar has 0 expert-panel submissions.	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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