rs137854538

chr20-58909553-G-Achr20-58909553-G-C

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.692G>A(p.Arg231His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R231C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.47

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr20-58909552-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 816910.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, 0.977
• PP5: Variant 20-58909553-G-A is Pathogenic according to our data. Variant chr20-58909553-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58909553-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4	c.2621G>A	p.Arg874His	missense_variant	9/13	ENST00000371100.9
GNAS	NM_000516.7	c.692G>A	p.Arg231His	missense_variant	9/13	ENST00000371085.8
GNAS	NM_016592.5	c.*598G>A		3_prime_UTR_variant	9/13	ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9	c.2621G>A	p.Arg874His	missense_variant	9/13	5	NM_080425.4
GNAS	ENST00000371085.8	c.692G>A	p.Arg231His	missense_variant	9/13	1	NM_000516.7
GNAS	ENST00000371075.7	c.*598G>A		3_prime_UTR_variant	9/13	1	NM_016592.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudohypoparathyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2001

- -

Pseudohypoparathyroidism type I A Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Genetics of Obesity Study, University of Cambridge

Jun 01, 2020

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 28, 2022

This variant disrupts the p.Arg231 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11600516, 25044890, 30349702). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects GNAS function (PMID: 8702665). 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. ClinVar contains an entry for this variant (Variation ID: 15946). This missense change has been observed in individuals with Albright’s hereditary osteodystrophy and/or pseudohypoparathyroidism (PMID: 8702665, 11450852). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 231 of the GNAS protein (p.Arg231His). For these reasons, this variant has been classified as Pathogenic. -

GNAS-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Aug 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D
Vest4		0.96
MutPred		0.82		Gain of ubiquitination at K876 (P = 0.0609);.;.;.;.;.;
MVP		1.0
MPC		3.5
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.97

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: rs137854538; hg19: chr20-57484608; COSMIC: COSV55676360; COSMIC: COSV55676360;