chr20-58909737-C-T

Variant names:

• chr20-58909737-C-T
• rs137854535
• NM_080425.4:c.2701C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_080425.4(GNAS):​c.2701C>T​(p.Arg901Trp) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R901A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_080425.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 1.90
• Publications: 12 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_080425.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-58909737-CG-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 15942.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15941.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.2701C>T	p.Arg901Trp	missense	Exon 10 of 13	NP_536350.2
	GNAS	NM_000516.7	MANE Select	c.772C>T	p.Arg258Trp	missense	Exon 10 of 13	NP_000507.1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*678C>T		3_prime_UTR	Exon 10 of 13	NP_057676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2701C>T	p.Arg901Trp	missense	Exon 10 of 13	ENSP00000360141.3
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.772C>T	p.Arg258Trp	missense	Exon 10 of 13	ENSP00000360126.3
	GNAS	ENST00000676826.2		c.2704C>T	p.Arg902Trp	missense	Exon 10 of 13	ENSP00000504675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000716 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Sep 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects GNAS function (PMID: 9727013, 34614324). 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. ClinVar contains an entry for this variant (Variation ID: 15941). This variant is also known as c.775C>T (p.Arg259Trp). 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. This variant is not present in population databases (gnomAD no frequency). 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).

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GNAS: PM2, PM5, PS4:Moderate, PM6:Supporting, PP2, PP3, PS3:Supporting

Nov 09, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Pseudohypoparathyroidism type I A Pathogenic:2

Jun 01, 2020

Genetics of Obesity Study, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 30, 2024

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pseudopseudohypoparathyroidism Pathogenic:2

Sep 11, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 06, 2017

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability; small stature

Inborn genetic diseases Pathogenic:1

May 17, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GNAS-related disorder Pathogenic:1

Feb 05, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 34614324, 9727013). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015941 /PMID: 9727013 /3billion dataset). The variant has been previously reported as de novo in a similarly affected individual (PMID: 28708303). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 28708303, 34614324, 9727013). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 9727013). Different missense changes at the same codon (p.Arg258Ala, p.Arg258Gln, p.Arg258Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015942, VCV000453009, VCV001065888 /PMID: 29095814, 34614324 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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