rs137854538

Variant names:

• chr20-58909553-G-A
• rs137854538
• NM_000516.7:c.692G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58909553-G-A
• chr20-58909553-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 Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 helix (size 9) in uniprot entity GNAS2_HUMAN there are 5 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 chr20-58909552-C-T 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, 0.977
• 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 rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.692G>A	p.Arg231His	missense_variant	Exon 9 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*598G>A		3_prime_UTR_variant	Exon 9 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.692G>A	p.Arg231His	missense_variant	Exon 9 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2624G>A	p.Arg875His	missense_variant	Exon 9 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2579G>A	p.Arg860His	missense_variant	Exon 8 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.695G>A	p.Arg232His	missense_variant	Exon 9 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.650G>A	p.Arg217His	missense_variant	Exon 8 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.518G>A	p.Arg173His	missense_variant	Exon 9 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.518G>A	p.Arg173His	missense_variant	Exon 10 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.518G>A	p.Arg173His	missense_variant	Exon 9 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.473G>A	p.Arg158His	missense_variant	Exon 8 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.473G>A	p.Arg158His	missense_variant	Exon 9 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.473G>A	p.Arg158His	missense_variant	Exon 8 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.473G>A	p.Arg158His	missense_variant	Exon 8 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.473G>A	p.Arg158His	missense_variant	Exon 8 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.473G>A	p.Arg158His	missense_variant	Exon 8 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.473G>A	p.Arg158His	missense_variant	Exon 8 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*598G>A		3_prime_UTR_variant	Exon 9 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*553G>A		3_prime_UTR_variant	Exon 8 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. For these reasons, this variant has been classified as Pathogenic. 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). -

Mar 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (PMID: 8702665); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11450852, 31886927, 34614324, 9159128, 8702665, 35497370, 30674755, 20979189) -

Pseudohypoparathyroidism Pathogenic:1

Jan 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pseudohypoparathyroidism type I A Pathogenic:1

Jun 01, 2020

Genetics of Obesity Study, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

GNAS-related disorder Pathogenic:1

Aug 03, 2023

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

Significance: Pathogenic

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	0.53	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
MutationAssessor	Pathogenic	4.5	.;.;.;H;.;.
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;