20-58909365-C-T

Variant names:

• chr20-58909365-C-T
• rs11554273
• NM_000516.7:c.601C>T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000516.7(GNAS):​c.601C>T​(p.Arg201Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 4.12

Genes affected

GNAS (HGNC:4392): (GNAS complex locus) This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5' exons. Some transcripts contain a differentially methylated region (DMR) at their 5' exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a binding_site (size 7) in uniprot entity GNAS2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000516.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-58909365-C-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in the GNAS gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 64 curated benign missense variants. Gene score misZ: 2.6546 (below the threshold of 3.09). Trascript score misZ: 4.8361 (above the threshold of 3.09). GenCC associations: The gene is linked to ACTH-independent macronodular adrenal hyperplasia 1, pseudohypoparathyroidism type 1B, pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia, pseudopseudohypoparathyroidism, McCune-Albright syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 20-58909365-C-T is Pathogenic according to our data. Variant chr20-58909365-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58909365-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.601C>T	p.Arg201Cys	missense_variant	Exon 8 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*507C>T		3_prime_UTR_variant	Exon 8 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.601C>T	p.Arg201Cys	missense_variant	Exon 8 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2533C>T	p.Arg845Cys	missense_variant	Exon 8 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2488C>T	p.Arg830Cys	missense_variant	Exon 7 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.604C>T	p.Arg202Cys	missense_variant	Exon 8 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.559C>T	p.Arg187Cys	missense_variant	Exon 7 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.427C>T	p.Arg143Cys	missense_variant	Exon 8 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.427C>T	p.Arg143Cys	missense_variant	Exon 9 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.427C>T	p.Arg143Cys	missense_variant	Exon 8 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.382C>T	p.Arg128Cys	missense_variant	Exon 8 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*507C>T		3_prime_UTR_variant	Exon 8 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*462C>T		3_prime_UTR_variant	Exon 7 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461360 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

McCune-Albright syndrome Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 23, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Sep 08, 2023	The GNAS c.601C>T (p.Arg201Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in numerous patients with McCune Albright Syndrome, with/without polyostotic fibrous dysplasia (Sargin H et al., PMID: 16543670; Lumborso S et al., PMID: 15126527, Caspari L et al., PMID: 22692721; Narumi S et al., PMID: 23536913). This variant is only observed on 2/152140 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GNAS function. This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters (ClinVar Variation ID: 15933). Functional studies show that the GNAS c.601C>T (p.Arg201Cys) variant leads to elevated expression of Wnt and increases the phosphorylation of ERK1/2 MAPK, cell proliferation, and tumor growth in animal models, indicating that this variant impacts protein function (Wilson CH et al., PMID: 20531296; More A et al., PMID: 35879396). Other variants in the same codon, including p.Arg201His, have been reported in affected individuals and are considered pathogenic/likely pathogenic (Riminucci M et al., PMID: 10571700, Fragoso MCBV et al., PMID: 12727968, ClinVar ID's: 15945, 210045, 15937, 15934). GNAS c.601C>T (p.Arg201Cys) is one of the most frequently occurring variants in McCune Albright Syndrome (Lumborso S et al., PMID: 15126527; Narumi S et al., PMID: 23536913; Shi RR et al., PMID: 23503642). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the GNAS c.601C>T (p.Arg201Cys) variant is classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Feb 14, 2014	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the GNAS protein (p.Arg201Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with McCune-Albright syndrome, as a somatic mosaic variant (PMID: 16543670, 17873334, 20197676, 27506760). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 15933). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GNAS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GNAS function (PMID: 2549426). This variant disrupts the p.Arg201 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15126527, 27506760). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

ACTH-independent macronodular adrenal hyperplasia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 23, 2014

- -

Pseudohypoparathyroidism type 1B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Sep 22, 2024

- -

Pituitary adenoma 3, multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 23, 2014

- -

Sex cord-stromal tumor Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 23, 2014

- -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Mar 04, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.3	.;.;.;.;H;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D;D;.;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.011	D;D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;D;.;D
Vest4		0.84
MutPred		0.91		Loss of sheet (P = 0.0817);.;.;.;.;.;.;
MVP		1.0
MPC		3.7
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11554273; hg19: chr20-57484420; COSMIC: COSV55670339; COSMIC: COSV55670339;