GNAS c.601C>T, p.(Arg201Cys)

27 criteria with recorded statuses: 4 met · 15 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/Ac.601C>T (p.Arg201Cys) is a missense variant that does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus) required for PVS1 applicability under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴

Evidence considered

• Missense substitution at codon 201
• variant bucket classified as 'other' by PVS1 variant assessment.

Sources

pvs1_generic_framework ↗

PS1 N/ANo evidence of a different nucleotide change producing the same p.Arg201Cys substitution was identified. The only known nucleotide change yielding R201C is c.601C>T (CGT→TGT). Details ▾Hide ▴

Evidence considered

• No alternative nucleotide variant detected at this codon producing the same amino acid change.

PS2 N/AMcCune-Albright syndrome is a postzygotic somatic mosaic disorder; the variant is not observed as a germline de novo event with confirmed maternity/paternity. PS2 applies only to germline de novo variants. Details ▾Hide ▴

Evidence considered

• Postzygotic somatic mutation
• no germline de novo observation.

PM5 N/APM5 applies to novel missense variants at an amino acid residue where a different pathogenic missense change has been established. R201C (c.601C>T) is itself an established pathogenic variant — it is not a novel change at codon 201. The classic PM5 paradigm is directed at previously unreported missense changes, not well-characterized pathogenic variants. Details ▾Hide ▴

Evidence considered

• R201C is a well-established activating mutation
• not a novel variant.
• pm5_candidates.json: unable to confirm classic same-residue PM5 semantics
• 0 candidates harvested.

PM6 N/APM6 requires a de novo germline observation with confirmed maternity/paternity. McCune-Albright syndrome is caused by postzygotic somatic mutations; no germline de novo observation exists for this variant. Details ▾Hide ▴

Evidence considered

• Postzygotic somatic mosaic disorder
• no germline de novo observation.

BP3 N/AVariant is a single-nucleotide missense substitution, not an in-frame deletion/insertion. Details ▾Hide ▴

Evidence considered

• Missense substitution
• BP3 applies to in-frame indels.

BP7 N/Ac.601C>T is a missense variant (p.Arg201Cys), not a synonymous variant with no predicted splice impact. BP7 applies exclusively to synonymous variants. Details ▾Hide ▴

Evidence considered

• Missense variant
• BP7 applies to synonymous variants only.

PS5 N/APS5 applies to de novo germline variants with confirmed maternity/paternity but without identity-by-descent confirmation. No such evidence exists for this postzygotic somatic mutation. Details ▾Hide ▴

Evidence considered

• Postzygotic somatic variant
• PS5 paradigm does not apply.

Identifiers

Gene

GNAS

Transcript

NM_000516.5

Coding (HGVS c.)

NM_000516.5:c.601C>T

Protein (HGVS p.)

NP_000507.1:p.(Arg201Cys)

GRCh38

chr20:58909365 C>T

GRCh37

chr20:57484420 C>T

ClinVar

3376616, 15933

Gene diagram

Every interpreted variant in GNAS, mapped onto the exon structure of NM_000516.5. Select a row to find it on the plot.

By genetic ancestry

Statements

SpliceAI and Pangolin

Other predictors

REVEL

0.943

BayesDel

0.543

How the predictions were used

PP3 SupportingMultiple in silico tools predict a damaging effect. REVEL score is 0.943 (highly deleterious), BayesDel score is 0.543. SpliceAI predicts no splice impact (max delta=0.00), consistent with a missense effect rather than splicing defect. The high REVEL score supports a pathogenic role. Details ▾Hide ▴

Evidence considered

• REVEL score: 0.943 (highly deleterious).
• BayesDel score: 0.543.
• SpliceAI max delta: 0.00 (no predicted splice effect).

Sources

revelbayesdelspliceai ↗

BP4 Multiple in silico tools predict a damaging effect: REVEL score 0.943 (highly deleterious), BayesDel score 0.543. No computational evidence supports a benign interpretation. BP4 is contradicted. Details ▾Hide ▴

Evidence considered

• REVEL: 0.943 (deleterious prediction).
• BayesDel: 0.543 (damaging prediction).

Sources

revelbayesdel

BP7 N/Ac.601C>T is a missense variant (p.Arg201Cys), not a synonymous variant with no predicted splice impact. BP7 applies exclusively to synonymous variants. Details ▾Hide ▴

Evidence considered

• Missense variant
• BP7 applies to synonymous variants only.

Statement

7 paper records listed. 6 cited in the classification.

Cited in the classification

• Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome--a European Collaborative Study.

  Lumbroso S et al. · 2004 May

  Lumbroso et al. analyzed 113 patients with signs of McCune-Albright syndrome using a sensitive PCR-based method. Activating Gsα mutations were identified in 43% of patients; R201C (cysteine substitution) was found in 15 of the 49 mutation-positive cases, with R201H accounting for the remaining 34. The mutation was detected in 46% of blood samples from patients with the classic triad and in >90% of affected tissue samples.

  → PM1 Names this variant
  PMID 15126527 ↗
  Source detail

  A mutation of arginine 201 in the Gsα protein was found in 49 of the 113 patients (43%), with a net preponderance of the substitution by histidine (n = 34) as opposed to cysteine (n = 15).

  Location Abstract; Results section; Tables 2-5.

  Context PCR-based enrichment assay with selective EagI digestion; sequencing of 174 tissue samples from 113 patients across European centers.

• Genetic diagnosis of multiple affected tissues in a patient with McCune-Albright syndrome.

  Zhou J et al. · 2007 Apr

  Zhou et al. identified the Arg201Cys (R201C) mutation in peripheral blood and bone tissue of a 32-year-old Chinese man with McCune-Albright syndrome presenting with polyostotic fibrous dysplasia, café-au-lait spots, and acromegaly. The mutation was absent from skin and pleura samples, consistent with the mosaic distribution of this postzygotic somatic mutation.

  → PM1 Names this variant
  PMID 17873334 ↗
  Source detail

  An Arg201Cys (R201C) mutation was found in genomic DNA which was isolated from peripheral blood and the bone tissue (from the left ilium). This is a missense point mutation (CGT→TGT) leading to the substitution of Cys for Arg at amino acid 201.

  Location Abstract; Results, 'Confirmation of gene mutation' section.

  Context Direct Sanger sequencing of Gsα exons 8 and 9 from peripheral blood, bone, skin, and pleura samples in a single MAS patient.

• The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways.

  Wilson et al. demonstrated that GNAS R201C promotes intestinal tumorigenesis in Apc(Min/+) mice. Transgenic expression of R201C led to constitutive activation of Wnt/β-catenin and ERK1/2 MAPK signaling pathways, directly establishing the oncogenic potential of this specific mutation.

  → PS3 → PM1 Names this variant
  PMID 20531296 ↗
  Source detail

  The common mutations of GNAS that have been identified in tumours, including R201C, R201H and Q227R, are thought to inhibit GTP hydrolysis and result in the constitutive activation of Gsα and cAMP synthesis.

  Location Introduction; Results sections throughout.

  Context Transgenic mouse model (Apc Min/+ background) with GNAS R201C expression; intestinal tumorigenesis assay.

• GNAS mutations identify a set of right-sided, RAS mutant, villous colon cancers.

  This study evaluated GNAS activating mutations in colorectal cancer, finding recurrent mutations at codon 201 (R201C and R201H). GNAS mutations were identified in right-sided, RAS-mutant, villous colon cancers. Both R201C and R201H result in constitutive activation of Gsα and autonomous cAMP production.

  → PM1 Names this variant
  PMID 24498230 ↗
  Source detail

  One of these genes was GNAS, in which we found recurrent mutations at codon 201, that altered the highly conserved Arg 201 to either cysteine (R201C) or histidine (R201H).

  Location Introduction.

  Context Exome sequencing and targeted pyrosequencing of colorectal cancer samples.

• GNAS mutation as an alternative mechanism of activation of the Wnt/β-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type.

  Nomura et al. identified activating GNAS R201C mutations in 5 of 26 (19.2%) gastric adenocarcinomas of the fundic gland type (GAFG). GNAS mutations were associated with nuclear β-catenin expression and occurred almost exclusively from Wnt pathway component gene mutations, suggesting GNAS R201C activates Wnt/β-catenin signaling as an alternative oncogenic mechanism.

  → PM1 Names this variant
  PMID 25288233 ↗
  Source detail

  Activating mutations in GNAS were found in 5 (19.2%) of 26 GAFGs, all of which harbored R201C mutations.

  Location Abstract; Results section.

  Context Direct sequencing of GNAS exons 8-9, KRAS exon 2, and Wnt pathway genes from formalin-fixed paraffin-embedded GAFG tumor samples; immunohistochemistry for β-catenin.

• GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours.

  Landis CA et al. · 1989 Aug 31

  Landis et al. identified somatic mutations in Gsα (including R201C and R201H) in growth hormone-secreting human pituitary tumors that inhibit GTPase activity and constitutively activate adenylyl cyclase. This is the foundational paper establishing R201C as a gain-of-function activating mutation.

  → PS3 → PM1 Names this variant
  PMID 2549426 ↗
  Source detail

  A subset of growth hormone-secreting human pituitary tumours carries somatic mutations that inhibit GTPase activity of a G protein alpha chain, alpha(s). The resulting activation of adenylyl cyclase bypasses the cells' normal requirement for trophic hormone.

  Location Abstract; cited universally as the discovery of R201C activating mutation.

  Context GTPase activity assay and adenylyl cyclase stimulation in human pituitary tumor samples.

Other recorded publications

• Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

  Richards et al. 2015 provides the ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methodology document and does not mention any specific variant, gene, or clinical case.

  Does not name this variant
  PMID 25741868 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

• ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/15933/
• gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/20-57484420-C-T?dataset=gnomad_r2_1
• gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr20-58909365-C-T?dataset=gn…
• gnomAD-Canada ↗http://192.168.4.76:8001/variant/20-58909365-C-T
• SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000516.5%3Ac.601C…
• OncoKB ↗www.oncokb.org/gene/GNAS/R201C
• COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=GNAS+c.601C%3ET
• Cancer hotspots ↗www.cancerhotspots.org/

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.