NM_000516.7:c.34C>T

Variant names:

• chr20-58891760-C-T
• rs797045046
• NM_000516.7:c.34C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000516.7(GNAS):​c.34C>T​(p.Gln12*) variant causes a stop gained 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 (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAS NM_000516.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.79

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 148 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-58891760-C-T is Pathogenic according to our data. Variant chr20-58891760-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 209158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58891760-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.34C>T	p.Gln12*	stop_gained	Exon 1 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*43-3852C>T		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.34C>T	p.Gln12*	stop_gained	Exon 1 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000354359.12	c.34C>T	p.Gln12*	stop_gained	Exon 1 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.34C>T	p.Gln12*	stop_gained	Exon 1 of 12	1		ENSP00000360136.3
GNAS	ENST00000371075.7	c.*43-3852C>T		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-3852C>T		intron_variant	Intron 1 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-3852C>T		intron_variant	Intron 1 of 11	5		ENSP00000360143.4
GNAS	ENST00000470512.6	c.-39+2407C>T		intron_variant	Intron 1 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.-39+2211C>T		intron_variant	Intron 2 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.-38-3852C>T		intron_variant	Intron 1 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-3852C>T		intron_variant	Intron 1 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-3852C>T		intron_variant	Intron 2 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.-39+2407C>T		intron_variant	Intron 1 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.-39+2852C>T		intron_variant	Intron 1 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.-39+2211C>T		intron_variant	Intron 1 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.-39+2942C>T		intron_variant	Intron 1 of 11	5		ENSP00000499332.2
GNAS	ENST00000461152.6	c.*51+971C>T		intron_variant	Intron 1 of 2	5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*43-3852C>T		intron_variant	Intron 1 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1113852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 551478

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudopseudohypoparathyroidism Pathogenic:2

Apr 06, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This GNAS variant has been identified in multiple individuals with a clinical presentation consistent with a GNAS-related condition. It is absent from a large population dataset, and has been reported in ClinVar (Variation ID 209158). This nonsense variant results in a premature stop codon in exon 1 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic. -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000209158, PMID:11092390). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Jul 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21525160, 11092390, 23533243, 27703483, 31886927, 33144682, 29059381) -

May 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with GNAS-related conditions (PMID: 11092390, 21525160, 23533243, 27703483, 29059381, 31886927, 33144682). This sequence change creates a premature translational stop signal (p.Gln12*) in the GNAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNAS are known to be pathogenic (PMID: 11784876, 23281139, 23796510, 25802881). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 209158). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Mar 22, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1857451:ACTH-independent macronodular adrenal hyperplasia 1;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C3494506:Pseudohypoparathyroidism type I A;C4540135:Pituitary adenoma 3, multiple types Pathogenic:1

Sep 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudohypoparathyroidism type I A Pathogenic:1

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss-of-function has been associated with the hypoparathyroidism phenotypes (PMID: 10980525), while gain-of-function has been reported for somatic variants in cancers (PMID: 11588148). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0113 - This gene is known to be imprinted and the imprinting can be transcript dependent (OMIM, PMID: 23884777). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 29072892). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other premature termination codon variants within the first 102 nucleotides comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, PMID: 17164301). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with pseudohypoparathyroidism Ia and pseudopseudohypoparathyroidism (PMID: 29059381, 29379892). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

GNAS-related disorder Pathogenic:1

Feb 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GNAS c.34C>T variant is predicted to result in premature protein termination (p.Gln12*). This variant has been reported in many individuals to be pathogenic for pseudohypoparathyroidism (PHP) or progressive osseous heteroplasia (POH); it was reported to have occurred de novo in multiple patients (Richard et al. 2013. PubMed ID: 23884777; Eddy et al. 2000. PubMed ID: 11092390; Salemi P et al 2018. PubMed ID: 29059381). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Nonsense variants in GNAS are expected to be pathogenic. In summary, this variant is interpreted as pathogenic GNAS-related disorders. -

Pseudohypoparathyroidism;C0033835:Pseudopseudohypoparathyroidism Pathogenic:1

Oct 07, 2014

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 21-year-old female with IUGR, mild motor delay, intellectual disability, hearing loss, mild Tourette/tics, short stature, and irregular phalanges. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.63
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs797045046; hg19: chr20-57466815;