LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000516.7:c.602G>A
GNAS
· NP_000507.1:p.(Arg201His)
· NM_000516.7
GRCh37: chr20:57484421 G>A
·
GRCh38: chr20:58909366 G>A
Gene:
GNAS
Transcript:
NM_000516.7
Final call
Pathogenic
PS3 moderate
PM1 moderate
PM2 supporting
PM6 supporting
PP3 strong
Variant details
Gene
GNAS
Transcript
NM_000516.7
Protein
NP_000507.1:p.(Arg201His)
gnomAD AF
2.4797005513614176e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic support: PS3 moderate, based on variant-specific GNAS R201H activation and pancreatic phenotypes in vivo.
2
Pathogenic support: PM1 moderate, because GNAS residue R201 is a recurrent activating mutational hotspot.
3
Pathogenic support: PM2 supporting, because gnomAD v4.1 frequency is 2.4797e-05 and below the 0.0001 threshold.
4
Pathogenic support: PM6 supporting, because the exact variant was reported as a postzygotic mosaic mutation without confirmed parental testing.
5
Pathogenic support: PP3 strong, because REVEL 0.969 exceeds the 0.932 strong threshold.
Final determination:
Under the generic ACMG/AMP 2015 fallback, one strong-equivalent criterion plus two moderate and two supporting pathogenic criteria yields Pathogenic; no benign rule is satisfied.
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: the record confirms p.Arg201His but does not document a different nucleotide change producing the same amino-acid substitution. |
PMID:1594625
|
| PS2 | Not met | Not met: the variant was postzygotic mosaic, with no documented confirmation of both maternity and paternity required for PS2. |
PMID:1594625
|
| PS3 | Met | Met, moderate: exact GNAS R201H mice showed elevated cAMP, activated PKA signaling, and tumors in 8/8 combined-model mice, with survival P<0.001. |
PMID:26257060
|
| PS4 | Not assessed | Not assessed: gnomAD provides 40/1,613,098 control alleles, but no paired affected-case frequency is available to calculate the required OR >5.0 and confidence interval. |
gnomad_v2
gnomad_v4
|
| PM1 | Met | Met, moderate: R201 is a statistically significant GNAS hotspot, with all cohort GNAS mutations confined to R201 and gnomAD v4.1 AF 2.4797e-05. |
hotspots
PMID:24855271
gnomad_v4
|
| PM2 | Met | Met at supporting strength: gnomAD v4.1 AF is 2.4797e-05, below the <=0.0001 PM2 supporting threshold, with zero homozygotes. |
gnomad_v2
gnomad_v4
|
| PM3 | N/A | Not applicable: PM3 requires a recessive disorder and a pathogenic variant confirmed in trans, neither of which is established for this mosaic activating GNAS variant. |
PMID:1594625
|
| 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: p.Arg201Cys and p.Arg201Gly are same-residue comparators, but their established pathogenic status is not documented in the available evidence. |
PMID:24855271
clinvar
|
| PM6 | Met | Met, supporting: the exact variant was reported as a postzygotic mosaic mutation in an affected patient without confirmed parental testing. |
PMID:1594625
|
| PP1 | Not assessed | Not assessed: no multiple affected relatives or informative cosegregation data were reported for this mosaic variant. |
PMID:1594625
|
| PP2 | Not assessed | Not assessed: recurrent GNAS missense activation is shown, but gene-wide low benign missense variation is not established. |
PMID:24855271
PMID:26257060
PMID:28868010
gnomad_v4
|
| PP3 | Met | Met strong PP3: missense REVEL score 0.969 meets the >=0.932 strong threshold. |
revel
|
| PP4 | Not assessed | Not assessed: the current patient's phenotype and family history are not supplied, so specificity for a single genetic etiology cannot be judged. |
PMID:15126527
|
| PP5 | Not met | Not met: the exact ClinVar record has zero expert-panel submissions, so its non-expert Pathogenic label cannot trigger PP5. |
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 allele frequency is 2.4797e-05, far below the 0.05 BA1 threshold. |
gnomad_v2
gnomad_v4
|
| BS1 | Not met | Not met: the maximum observed gnomAD v4.1 ancestry frequency is 6.75676e-05, below the generic 0.01 BS1 threshold. |
gnomad_v2
gnomad_v4
|
| BS2 | Not assessed | Not assessed: gnomAD shows zero homozygotes but does not document healthy adult status, age, or full early-age penetrance. |
gnomad_v2
gnomad_v4
|
| BS3 | Not assessed | Not assessed: no well-established no-effect assay was identified, while the available variant-specific model showed constitutive activation and elevated cAMP. |
PMID:26257060
|
| BS4 | Not assessed | Not assessed: no affected relatives were tested, so no informative lack-of-segregation result is available. |
PMID:1594625
|
| BP1 | Not met | Not met: GNAS disease evidence centers on activating missense variants, including R201H, not primarily truncating variants. |
PMID:26257060
PMID:28868010
PMID:24855271
|
| BP2 | Not assessed | Not assessed: no pathogenic second variant or phase result establishes the required cis or trans relationship for BP2. |
PMID:1594625
|
| 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 0.969 exceeds the <=0.29 BP4 supporting threshold. |
revel
|
| BP5 | Not met | Not met: no same-case alternate molecular basis is documented alongside the variant; the KrasG12D evidence is from a mouse model. |
PMID:28868010
PMID:26257060
|
| BP6 | Not met | Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present, and expert-panel submissions total zero. |
clinvar
|
| BP7 | N/A | Not applicable: BP7 requires a synonymous variant, and this is a missense variant. |
generic_acmg_combination_rules
|
Disclaimer:
The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.