Variant classification summary

NM_000516.5:c.602G>A

GNAS · NP_000507.1:p.(Arg201His) · NM_000516.5

GRCh37: chr20:57484421 G>A · GRCh38: chr20:58909366 G>A

Gene: GNAS Transcript: NM_000516.5

Final call

Pathogenic

PS3 strong PS4 moderate PM1 moderate PM2 supporting PM5 moderate PP3 supporting PP5 supporting

Variant details

Gene

GNAS

Transcript

NM_000516.5

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

NM_000516.5:c.602G>A (p.Arg201His) is a well-characterized activating missense variant in the GNAS gene. Functional studies demonstrate that this substitution reduces GTPase activity approximately 30-fold, causing constitutive activation of adenylyl cyclase and downstream cAMP signaling (PS3_Strong).

2

The variant resides at codon 201 within the GTPase domain of Gsα, a critical functional domain and established mutational hotspot (PM1_Moderate).

3

A different pathogenic missense change at the same residue, p.Arg201Cys, is well-established in McCune-Albright syndrome and functionally equivalent (PM5_Moderate).

4

The variant has been reported in numerous individuals with McCune-Albright syndrome; Lumbroso et al. identified R201H in 34 of 113 patients with MAS features (PS4_Moderate).

5

The variant is extremely rare in population databases (gnomAD v2.1 AF=0.00159%), supporting pathogenicity (PM2_Supporting).

6

Computational predictors strongly support a deleterious effect: REVEL score 0.969, BayesDel score 0.612 (PP3_Supporting).

7

ClinVar classifies this variant as Pathogenic (Variation ID 15934) with consensus across multiple clinical laboratories (PP5_Supporting).

8

Applying the generic ACMG/AMP 2015 combination rules: one Strong criterion (PS3) plus three Moderate criteria (PM1, PM5, PS4) and three Supporting criteria (PM2, PP3, PP5) meets the threshold for Pathogenic classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

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	NM_000516.5:c.602G>A is a missense variant (p.Arg201His) that does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 application under the ClinGen SVI PVS1 decision framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	PS1 requires the same amino acid change (p.Arg201His) resulting from a different nucleotide change. The canonical R201H alteration arises exclusively from c.602G>A; no alternative nucleotide substitution yielding p.Arg201His has been reported. Other pathogenic changes at codon 201 result in different amino acid substitutions (R201C, R201S, R201G, R201L).	PMID:15126527
PS2	Not met	No confirmed de novo occurrence with both maternity and paternity confirmed has been identified for this variant in a germline context. GNAS p.Arg201His is predominantly a postzygotic somatic mosaic mutation causing McCune-Albright syndrome.	PMID:1594625 PMID:15126527
PS3	Met	Well-established functional studies demonstrate that p.Arg201His constitutively activates Gsα. Landis et al. (PMID:2549426) showed that R201H substitution reduces GTPase activity approximately 30-fold, resulting in constitutive adenylyl cyclase activation. Taki et al. (PMID:26257060) demonstrated that transgenic expression of GNAS R201H in murine pancreas elevates cAMP levels, induces ductal dilation, and cooperates with KrasG12D to promote tumorigenesis recapitulating human IPMN. Two independent publications with direct variant-specific functional characterization satisfy PS3 at strong strength.	PMID:2549426 PMID:26257060 PMID:1594625 oncokb
PS4	Met	This variant has been reported in numerous unrelated individuals with McCune-Albright syndrome and related phenotypes. Lumbroso et al. (PMID:15126527) identified R201H in 34 of 113 patients with MAS signs, representing the most common activating mutation. The variant is classified as Pathogenic in ClinVar by multiple clinical laboratories (Variation ID 15934). gnomAD population frequency is extremely low (AF=0.00159%; 4/251,454 alleles in v2.1), demonstrating significant enrichment in affected individuals compared to population controls. Strength is calibrated to moderate given the predominantly somatic mosaic context.	PMID:15126527 PMID:1594625 clinvar gnomad_v2
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. No CSPEC/VCEP or custom gene-specific framework defines this criterion for GNAS. The standard ACMG framework extends from PVS1 through BP7 only.	generic_acmg_combination_rules
PM1	Met	The variant resides at codon 201 within the GTPase domain of Gsα, a critical functional domain. Arg201 is the site of ADP-ribosylation by cholera toxin and is essential for intrinsic GTPase activity. The codon is a well-established mutational hotspot in McCune-Albright syndrome, pituitary adenomas, and other tumors. Cancerhotspots.org identifies this residue as statistically significant. The variant lies within a domain where essentially all reported missense changes are pathogenic.	PMID:1594625 PMID:2549426 oncokb
PM2	Met	This variant is present at extremely low frequency in population databases. gnomAD v2.1 exomes: allele frequency 1.59×10⁻⁵ (0.00159%; 4/251,454 alleles, 0 homozygotes). gnomAD v4.1: allele frequency 2.48×10⁻⁵ (40/1,613,098 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Met	A different missense change at the same amino acid residue (p.Arg201Cys, resulting from c.601C>T) is well-established as pathogenic. R201C is the second most common activating GNAS mutation in McCune-Albright syndrome and related disorders, with equivalent gain-of-function consequences. Lumbroso et al. (PMID:15126527) reported R201C in 15/113 patients. Both R201H and R201C are established activating mutations that disrupt GTPase activity and constitutively activate adenylyl cyclase.	PMID:15126527 PMID:2549426
PM6	Not met	PM6 applies when a variant is assumed de novo but without confirmation of paternity and maternity. No de novo germline report was identified for this variant. GNAS p.Arg201His in McCune-Albright syndrome is a postzygotic somatic mosaic event, not a germline de novo mutation.	PMID:1594625 PMID:15126527
PP1	Not met	No cosegregation data are available for this variant in a germline context. McCune-Albright syndrome is a sporadic disorder caused by postzygotic somatic mutations; familial inheritance is not expected.	PMID:1594625 PMID:15126527
PP2	Not assessed	PP2 requires that the gene has a low rate of benign missense variation and that missense variants are a common mechanism of disease. GNAS has a dual disease mechanism: gain-of-function missense variants cause McCune-Albright syndrome and related disorders, while loss-of-function variants (including truncating) cause pseudohypoparathyroidism. The gene-level constraint metrics for PP2 were not systematically evaluated for this assessment.
PP3	Met	Multiple lines of computational evidence support a deleterious effect. REVEL score is 0.969, which is strongly predictive of pathogenicity. BayesDel score is 0.612, consistent with a damaging prediction. SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for a missense variant not near splice junctions. The REVEL score in particular provides strong in silico support.	revel bayesdel spliceai
PP4	Not met	PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No patient-specific phenotype data are available for this assessment. This criterion is evaluated in the context of the individual being tested, not at the variant level.
PP5	Met	This variant is reported as Pathogenic in ClinVar (Variation ID 15934) by multiple clinical laboratories: 6 classify as Pathogenic and 3 as Likely pathogenic. While the aggregate review status is 'criteria provided, single submitter' (no expert panel review), the consensus across multiple independent laboratories provides supporting evidence for pathogenicity.	clinvar
BA1	Not met	BA1 requires allele frequency >1% in population databases. This variant has an allele frequency of 0.00159% in gnomAD v2.1 and 0.00248% in gnomAD v4.1, both far below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires allele frequency >0.3% in population databases. This variant has an allele frequency of 0.00159% in gnomAD v2.1 and 0.00248% in gnomAD v4.1, both far below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in healthy adults at significant frequency. This variant is present at only 4/251,454 alleles in gnomAD v2.1 with no homozygotes. The extremely low frequency does not support a benign interpretation. No evidence of healthy adult homozygotes or high-frequency carriers exists.	gnomad_v2 gnomad_v4
BS3	Not met	BS3 requires well-established functional studies showing no damaging effect. The functional data for p.Arg201His consistently demonstrate a gain-of-function activating effect: reduced GTPase activity (~30-fold), constitutive adenylyl cyclase activation, elevated cAMP, and promotion of tumorigenesis in vivo. The evidence supports pathogenicity, not benignity.	PMID:2549426 PMID:26257060 oncokb
BS4	Not met	BS4 requires lack of segregation in affected family members. No segregation data are available. McCune-Albright syndrome is a sporadic postzygotic disorder; lack of segregation is not informative for benignity.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. GNAS has a well-established gain-of-function disease mechanism through activating missense mutations (McCune-Albright syndrome, endocrine tumors) in addition to loss-of-function through truncating variants (pseudohypoparathyroidism). Missense variants at codon 201 are the primary cause of MAS.	PMID:1594625 PMID:15126527
BP2	Not met	BP2 requires observation in trans with a pathogenic variant in a gene associated with a recessive disorder. GNAS-related disorders are dominant; BP2 does not apply. No evidence of in trans configuration with another pathogenic GNAS variant exists.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score of 0.969 strongly predicts pathogenicity. BayesDel score of 0.612 supports a damaging effect. While SpliceAI predicts no splicing impact (delta 0.01), the overall in silico profile supports a deleterious effect, opposite of BP4 requirements.	revel bayesdel spliceai
BP5	Not met	BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No evidence of an alternative molecular diagnosis exists for cases carrying this variant. GNAS R201H is the established molecular cause in reported cases.
BP6	Not met	BP6 requires a reputable source to report the variant as benign. ClinVar classifies this variant as Pathogenic (Variation ID 15934). No reputable source reports it as benign.	clinvar
BP7	Not met	BP7 applies to synonymous variants with no predicted splice impact. NM_000516.5:c.602G>A is a missense variant producing p.Arg201His, not a synonymous change. BP7 is not applicable.

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