Variant classification summary

NM_000516.7:c.601C>T

GNAS · NP_000507.1:p.(Arg201Cys) · NM_000516.7

GRCh37: chr20:57484420 C>T · GRCh38: chr20:58909365 C>T

Gene: GNAS Transcript: NM_000516.7

Final call

Pathogenic

PS3 supporting PM1 moderate PM2 supporting PM5 moderate PP3 strong

Variant details

Gene

GNAS

Transcript

NM_000516.7

Protein

NP_000507.1:p.(Arg201Cys)

gnomAD AF

4.958165478772854e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 supporting shows R201C increased signaling and doubled intestinal adenoma formation in mice.

2

Pathogenic: PM1 moderate identifies Arg201 as a recurrent GNAS mutational hotspot without presented benign variation evidence.

3

Pathogenic: PM2 supporting reflects the extremely rare gnomAD filtering frequency of 1.24e-06.

4

Pathogenic: PM5 moderate is supported by the disease-associated, constitutively activating alternate p.Arg201His substitution.

5

Pathogenic: PP3 strong is supported by REVEL 0.943 exceeding the 0.932 strong threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong, two moderate, and two supporting pathogenic criteria 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	Not met	Not met: no previously established pathogenic GNAS Arg201Cys substitution caused by a different nucleotide change was documented; Arg201His is a different amino-acid change.	PMID:17873334 PMID:15126527
PS2	Not met	Not met: the reported p.Arg201Cys case was post-zygotic somatic mosaicism, with no confirmed maternity and paternity as required for PS2.	PMID:17873334 clinvar
PS3	Met	Met at supporting strength: R201C doubled intestinal adenomas from 30 ± 2.9 to 62 ± 5.2 in mice (P=0.0001), with concordant pathway-activation findings.	PMID:20531296
PS4	Not met	Not met: reviewed reports are case series without valid matched controls, so the required OR/RR >5.0 with a confidence interval excluding 1 cannot be established.	PMID:20531296 gnomad_v4
PM1	Met	Met at moderate strength: Arg201 is a statistically significant recurrent GNAS hotspot, with 49/113 syndrome patients carrying codon-201 mutations and only 8/1,613,500 gnomAD v4.1 alleles for this variant.	hotspots PMID:24498230 PMID:15126527 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: gnomAD v4.1 grpmax FAF is 1.24e-06, below the PM2 cutoff of 0.0001, with 8/1,613,500 alleles and no homozygotes.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: PM3 requires a recessive disorder, but this GNAS variant is documented in a mosaic/somatic activating-disease context rather than 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 at moderate strength: the alternate p.Arg201His occurred in 34/113 McCune-Albright patients, with no severity difference from Arg201Cys, and both substitutions constitutively activate Gsα.	PMID:15126527 PMID:24498230 PMID:17873334
PM6	Not met	Not met: available primary evidence describes post-zygotic somatic mosaicism, while the de novo submission signal lacks parental genotypes and germline pedigree details.	PMID:17873334 clinvar
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or cosegregating genotypes were reported for this sporadic mosaic case.	PMID:17873334
PP2	Not assessed	Not assessed: activating GNAS missense disease is documented, but no gene-wide evidence establishes a low rate of benign missense variation.	PMID:15126527 PMID:17873334
PP3	Met	Met: REVEL 0.943 meets the generic PP3 strong threshold of >=0.932 for this missense variant.	revel PMID:25741868
PP4	Not assessed	Not assessed: the current patient's phenotype and family history are not provided, preventing evaluation of phenotype specificity for a single genetic etiology.
PP5	Not met	Not met: ClinVar contains pathogenic assertions, but zero exact-variant expert-panel submissions are present, so ordinary laboratory and aggregate labels cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.24e-06, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.24e-06, well below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD shows 0 homozygotes and 8 alleles but does not document qualifying healthy adult individuals or their phenotypes.	gnomad_v4 gnomad_v2 PMID:25741868
BS3	Not assessed	Not assessed: no benign functional assay was identified, while the available R201C mouse study showed increased cAMP signaling and adenoma formation.	PMID:20531296
BS4	Not assessed	Not assessed: no affected relatives with negative variant testing or family segregation study was reported.
BP1	Not met	Not met: GNAS disease literature shows recurrent activating missense disease, including Arg201 mutations in 49/113 patients, rather than primarily truncating disease.	PMID:15126527 PMID:17873334 PMID:24498230
BP2	Not assessed	Not assessed: no cis/trans phase result or affected-proband observation with a second pathogenic variant is available for the required BP2 comparison.	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: REVEL 0.943 exceeds the generic BP4 supporting threshold of <=0.29 for this missense variant.	revel PMID:25741868
BP5	Not assessed	Not assessed: no case documents this exact variant together with a demonstrated alternate molecular basis for the relevant disease.
BP6	Not met	Not met: no exact-variant expert-panel benign or likely benign classification is present; ClinVar instead shows pathogenic submissions and zero 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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