rs137854539

Variant names:

• chr20-58903703-C-T
• rs137854539
• NM_000516.7:c.344C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000516.7(GNAS):​c.344C>T​(p.Pro115Leu) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P115S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.75
• Publications: 16 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: Pathogenic. The variant received 16 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, 9 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 chr20-58903702-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1459427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 20-58903703-C-T is Pathogenic according to our data. Variant chr20-58903703-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.344C>T	p.Pro115Leu	missense_variant	Exon 5 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*250C>T		3_prime_UTR_variant	Exon 5 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.344C>T	p.Pro115Leu	missense_variant	Exon 5 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2276C>T	p.Pro759Leu	missense_variant	Exon 5 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2231C>T	p.Pro744Leu	missense_variant	Exon 4 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.347C>T	p.Pro116Leu	missense_variant	Exon 5 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.302C>T	p.Pro101Leu	missense_variant	Exon 4 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.170C>T	p.Pro57Leu	missense_variant	Exon 5 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.170C>T	p.Pro57Leu	missense_variant	Exon 6 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.170C>T	p.Pro57Leu	missense_variant	Exon 5 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.125C>T	p.Pro42Leu	missense_variant	Exon 4 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.125C>T	p.Pro42Leu	missense_variant	Exon 5 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.125C>T	p.Pro42Leu	missense_variant	Exon 4 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.125C>T	p.Pro42Leu	missense_variant	Exon 4 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.125C>T	p.Pro42Leu	missense_variant	Exon 4 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.125C>T	p.Pro42Leu	missense_variant	Exon 4 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.125C>T	p.Pro42Leu	missense_variant	Exon 4 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*250C>T		3_prime_UTR_variant	Exon 5 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*205C>T		3_prime_UTR_variant	Exon 4 of 12	5		ENSP00000392000.2
GNAS	ENST00000461152.6	c.*300C>T		downstream_gene_variant		5		ENSP00000499274.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.000144 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudohypoparathyroidism Pathogenic:2

Jan 29, 2019

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Apr 14, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed 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: 12621129, 11600516, 16789628, 24850831, 21274345, 15070926, 31886927) -

Dec 16, 2022

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.Pro115 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21274345, 28296742, 29059381). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 15953). This variant is also known as p.Pro116Leu. This missense change has been observed in individuals with pseudohypoparathyroidism type 1a (PMID: 11600516, 23884777). 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 115 of the GNAS protein (p.Pro115Leu). -

Pseudopseudohypoparathyroidism Pathogenic:1

Oct 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.;.;.;D;.;.;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;M;.;.;.
PhyloP100		5.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-9.3	D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.029	D;T;D;.;D;T;T;D;.
Sift4G	Uncertain	0.044	D;D;D;D;T;T;T;T;D
Polyphen		1.0	D;.;.;.;.;D;.;D;.
Vest4		0.60
MutPred		0.55		Loss of catalytic residue at P758 (P = 0.0336);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.89
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: rs137854539; hg19: chr20-57478758;