20-58909737-C-T

Position:

• chr20-58909737-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_000516.7(GNAS):​c.772C>T​(p.Arg258Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R258Q) 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:8 U:1
• Conservation: PhyloP100: 1.90

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 16 ACMG points.

• PM1: In a turn (size 2) 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 chr20-58909738-G-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNAS. . Gene score misZ: 2.6546 (greater than the threshold 3.09). Trascript score misZ: 4.8361 (greater than threshold 3.09). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 64 curated benign missense variants. GenCC has associacion of the gene with 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, 0.75
• PP5: Variant 20-58909737-C-T is Pathogenic according to our data. Variant chr20-58909737-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58909737-C-T is described in Lovd as [Likely_pathogenic]. Variant chr20-58909737-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.772C>T	p.Arg258Trp	missense_variant	10/13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*678C>T		3_prime_UTR_variant	10/13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.772C>T	p.Arg258Trp	missense_variant	10/13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2704C>T	p.Arg902Trp	missense_variant	10/13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2659C>T	p.Arg887Trp	missense_variant	9/12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.775C>T	p.Arg259Trp	missense_variant	10/13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.730C>T	p.Arg244Trp	missense_variant	9/12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.598C>T	p.Arg200Trp	missense_variant	10/13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.598C>T	p.Arg200Trp	missense_variant	11/14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.598C>T	p.Arg200Trp	missense_variant	10/13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.553C>T	p.Arg185Trp	missense_variant	9/12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.553C>T	p.Arg185Trp	missense_variant	10/13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.553C>T	p.Arg185Trp	missense_variant	9/12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.553C>T	p.Arg185Trp	missense_variant	9/12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.553C>T	p.Arg185Trp	missense_variant	9/12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.553C>T	p.Arg185Trp	missense_variant	9/12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.553C>T	p.Arg185Trp	missense_variant	9/12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*678C>T		3_prime_UTR_variant	10/13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*633C>T		3_prime_UTR_variant	9/12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	GNAS: PM2, PM5, PS4:Moderate, PM6:Supporting, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2023	Published functional studies demonstrate a damaging effect as R258W causes a specific defect in activation (PMID: 9727013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9727013, 28708303, 31886927, 36835474, 27535533, 34614324) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 17, 2023	This variant is also known as c.775C>T (p.Arg259Trp). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 258 of the GNAS protein (p.Arg258Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GNAS-related conditions (PMID: 28708303, 31886927, 34614324). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 15941). 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 not expected to disrupt GNAS protein function. Experimental studies have shown that this missense change affects GNAS function (PMID: 9727013, 34614324). This variant disrupts the p.Arg258 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been observed in individuals with GNAS-related conditions (PMID: 29095814, 34614324), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Pseudohypoparathyroidism type I A Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Genetics of Obesity Study, University of Cambridge	Jun 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.54). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015941). A different missense change at the same codon (p.Arg258Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000453009). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Pseudopseudohypoparathyroidism Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 11, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	Jan 06, 2017	Intellectual disability; small stature -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;.;.;D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.012	D;D;T;T;T;T
Sift4G	Uncertain	0.043	D;D;T;T;T;T
Polyphen		1.0	D;.;.;D;.;P
Vest4		0.63
MutPred		0.66		Loss of disorder (P = 0.009);.;.;.;.;.;
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
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

Other links and lift over

dbSNP: rs137854535; hg19: chr20-57484792; COSMIC: COSV105009920; COSMIC: COSV105009920;