20-58909365-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_080425.4(GNAS):c.2530C>T(p.Arg844Cys) 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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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. R844L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GNAS
NM_080425.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:2

Conservation

PhyloP100: 4.12

Publications

322 publications found

Variant links:

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]

GNAS Gene-Disease associations (from GenCC):

McCune-Albright syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
progressive osseous heteroplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pseudohypoparathyroidism type 1B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
pseudohypoparathyroidism type 1C
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
pseudopseudohypoparathyroidism
Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
pseudohypoparathyroidism type 1A
Inheritance: Mitochondrial, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

GNAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_080425.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-58909365-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 15945.Status of the report is no_assertion_criteria_provided, 0 stars.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 15933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GNAS	NM_080425.4 link	c.2530C>T	p.Arg844Cys	missense_variant	Exon 8 of 13	ENST00000371100.9	NP_536350.2
GNAS	NM_000516.7 link	c.601C>T	p.Arg201Cys	missense_variant	Exon 8 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5 link	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
GNAS	ENST00000371100.9 link	c.2530C>T	p.Arg844Cys	missense_variant	Exon 8 of 13	5	NM_080425.4	ENSP00000360141.3
GNAS	ENST00000371085.8 link	c.601C>T	p.Arg201Cys	missense_variant	Exon 8 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2 link	c.2533C>T	p.Arg845Cys	missense_variant	Exon 8 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8 link	c.2488C>T	p.Arg830Cys	missense_variant	Exon 7 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12 link	c.604C>T	p.Arg202Cys	missense_variant	Exon 8 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7 link	c.559C>T	p.Arg187Cys	missense_variant	Exon 7 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6 link	c.427C>T	p.Arg143Cys	missense_variant	Exon 8 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6 link	c.427C>T	p.Arg143Cys	missense_variant	Exon 9 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2 link	c.427C>T	p.Arg143Cys	missense_variant	Exon 8 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 8 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 7 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7 link	c.*507C>T		3_prime_UTR_variant	Exon 8 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7 link	c.*462C>T		3_prime_UTR_variant	Exon 7 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

251470

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461360

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727026

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111544

Other (OTH)

AF:

0.00

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.233

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74316

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

McCune-Albright syndrome

Pathogenic:3Other:1

Feb 14, 2014

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

May 23, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Sep 08, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Pathogenic:2

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Mar 08, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACTH-independent macronodular adrenal hyperplasia 1

Pathogenic:1

May 23, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Pseudohypoparathyroidism type 1B

Pathogenic:1

Sep 22, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pituitary adenoma 3, multiple types

Pathogenic:1

May 23, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Sex cord-stromal tumor

Pathogenic:1

May 23, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.;D;.;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

0.0

.;.;.;.;H;.;.

PhyloP100

4.1

PrimateAI

Pathogenic

0.93

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

Vest4

0.84

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over