rs121913495

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000516.7(GNAS):c.602G>A(p.Arg201His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as 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: 0.000026 ( 0 hom. )

Consequence

GNAS
NM_000516.7 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 9.47

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a binding_site (size 7) in uniprot entity GNAS2_HUMAN there are 13 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-T is described in ClinVar as [Pathogenic]. Clinvar id is 15933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant where missense usually causes diseases, GNAS

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 20-58909366-G-A is Pathogenic according to our data. Variant chr20-58909366-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58909366-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GNAS	NM_080425.4 linkuse as main transcript	c.2531G>A	p.Arg844His	missense_variant	8/13	ENST00000371100.9
GNAS	NM_000516.7 linkuse as main transcript	c.602G>A	p.Arg201His	missense_variant	8/13	ENST00000371085.8
GNAS	NM_016592.5 linkuse as main transcript	c.*508G>A		3_prime_UTR_variant	8/13	ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	UniProt
GNAS	ENST00000371100.9 linkuse as main transcript	c.2531G>A	p.Arg844His	missense_variant	8/13	5	NM_080425.4	Q5JWF2-1
GNAS	ENST00000371085.8 linkuse as main transcript	c.602G>A	p.Arg201His	missense_variant	8/13	1	NM_000516.7	P63092-1
GNAS	ENST00000371075.7 linkuse as main transcript	c.*508G>A		3_prime_UTR_variant	8/13	1	NM_016592.5	O95467-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1460964

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726854

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 201 of the GNAS protein (p.Arg201His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with McCune‚ÄìAlbright syndrome, as a somatic mosaic variant (PMID: 15126527, 27506760). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 15934). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNAS protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	GNAS: PS4, PM5, PS3:Moderate, PM2:Supporting, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 20, 2020	PS3, PS4, PP3, PM2 -

McCune-Albright syndrome

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 23, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Oct 12, 2023	The GNAS c.602G>A (p.Arg201His) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with McCune-Albright syndrome (Pienkowski C et al., PMID: 9343290; Chevalier N et al., PMID: 26321108; Elli FM et al., PMID: 31620168; Román R et al., PMID: 15289771; Lumbroso S et al., PMID: 15126527; Cho EK et al., PMID: 27506760). This variant has been reported in the ClinVar database as a germline pathogenic by multiple submitters (ClinVar ID: 15934). This variant is only observed on 2/152134 alleles in the general population (gnomAD v3.1.2), indicating it is not a common variant. Another variant in the same codon, c.601C>T (p.Arg201Cys), has been reported in multiple affected individuals with McCune-Albright syndrome and is considered pathogenic (Lumbroso S et al., PMID: 15126527; Cho EK et al., PMID: 27506760; ClinVar ID: 15933). The GNAS c.602G>A (p.Arg201His) variant resides within a G-alpha domain, amino acids 41-388, of GNAS that is defined as a critical functional domain (Weinstein LS et al., PMID: 11588148; Tesmer JJ et al., PMID: 9417641). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on GNAS function. Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the GNAS c.602G>A (p.Arg201His) variant is classified as pathogenic. -

Adrenal cortex carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.602G>A (p.R201H) alteration is located in exon 8 (coding exon 8) of the GNAS gene. This alteration results from a G to A substitution at nucleotide position 602, causing the arginine (R) at amino acid position 201 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (4/251454) total alleles studied. The highest observed frequency was 0.01% (1/10078) of Ashkenazi Jewish alleles. This variant was reported in multiple individuals, and as mosaic in some with clinical features such as cafe au lait spots, premature menstruation, neonatal Cushing syndrome, thyroid disease, and others, all consistent with McCune Albright syndrome (Collins, 2003; Lumbroso, 2004; Lourenço, 2015; Coles, 2019). Two other alterations at the same codon, c.601C>A (p.R201S), c.601C>T (p.R201C), and c.601C>G (p.R201G), have been described in individuals with clinical features consistent with McCune Albright syndrome (Riminucci, 1999; Lumbroso, 2004; Jour, 2016). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Pseudohypoparathyroidism type I A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.602G>A;p.(Arg201His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 15934; PMID: 25719192; 25157968; 24855271; 23536913; 21835143; 16507630; 15126527; 12727968) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 23403822; 1517386) - PS3_moderate. The variant is present at low allele frequencies population databases (rs121913495– gnomAD 0.0001315%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (Clivar ID: 210045) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Gastric adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Pituitary adenoma 3, multiple types

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 23, 2014

- -

Breast neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Sex cord-stromal tumor

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 23, 2014

- -

Malignant melanoma of skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

ACTH-independent macronodular adrenal hyperplasia 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 23, 2014

- -

Pancreatic adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of uterine cervix

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

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

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

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

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

0.96

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.4

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

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.92

MutPred

0.90

Gain of catalytic residue at L846 (P = 0.0468);.;.;.;.;.;.;

MVP

1.0

MPC

3.5

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over