rs137854539

chr20-58903703-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 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

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 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 id is 1459427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, GNAS
• 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 [Likely_pathogenic]. Clinvar id is 15953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58903703-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4	c.2273C>T	p.Pro758Leu	missense_variant	5/13	ENST00000371100.9
GNAS	NM_000516.7	c.344C>T	p.Pro115Leu	missense_variant	5/13	ENST00000371085.8
GNAS	NM_016592.5	c.*250C>T		3_prime_UTR_variant	5/13	ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9	c.2273C>T	p.Pro758Leu	missense_variant	5/13	5	NM_080425.4
GNAS	ENST00000371085.8	c.344C>T	p.Pro115Leu	missense_variant	5/13	1	NM_000516.7
GNAS	ENST00000371075.7	c.*250C>T		3_prime_UTR_variant	5/13	1	NM_016592.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00310 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pseudohypoparathyroidism Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jan 29, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2001	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 16, 2022	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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2001

- -

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
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
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

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: rs137854539; hg19: chr20-57478758;