rs587776829

Positions:

• chr20-58909193-GCTGA-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000516.7(GNAS):​c.565_568del​(p.Asp189MetfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GNAS NM_000516.7 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14 U:1 O:1
• Conservation: PhyloP100: 9.35

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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-58909193-GCTGA-G is Pathogenic according to our data. Variant chr20-58909193-GCTGA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15938.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=11, Uncertain_significance=1}. Variant chr20-58909193-GCTGA-G is described in Lovd as [Pathogenic]. Variant chr20-58909193-GCTGA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_000516.7	c.565_568del	p.Asp189MetfsTer14	frameshift_variant	7/13	ENST00000371085.8
GNAS	NM_080425.4	c.2494_2497del	p.Asp832MetfsTer14	frameshift_variant	7/13	ENST00000371100.9
GNAS	NM_016592.5	c.*471_*474del		3_prime_UTR_variant	7/13	ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371085.8	c.565_568del	p.Asp189MetfsTer14	frameshift_variant	7/13	1	NM_000516.7
GNAS	ENST00000371100.9	c.2494_2497del	p.Asp832MetfsTer14	frameshift_variant	7/13	5	NM_080425.4
GNAS	ENST00000371075.7	c.*471_*474del		3_prime_UTR_variant	7/13	1	NM_016592.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pseudohypoparathyroidism Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 01, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	This sequence change creates a premature translational stop signal (p.Asp189Metfs*14) 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). This premature translational stop signal has been observed in individual(s) with GNAS-related conditions (PMID: 20427508). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 15938). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2022	Reported as a common pathogenic variant in association with disorders of GNAS inactivation (Haldeman-Englert et al., 2017); Published functional studies demonstrate a damaging effect (Weinstein et al., 1992; Inta et al., 2014); Frameshift 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29059381, 29072892, 24481334, 21525160, 24626099, 18553568, 15711092, 11784876, 12024004, 9876352, 30729047, 1505964, 20427508, 31793173, 31886927) -

Pseudohypoparathyroidism type 1B Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 24, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM1,PM2,PP5. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

Progressive osseous heteroplasia Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2008	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Dec 20, 2017

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2023

The c.565_568delGACT (p.D189Mfs*14) alteration, located in exon 7 (coding exon 7) of the GNAS gene, consists of a deletion of 4 nucleotides from position 565 to 568, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay._x000D_ _x000D_ Based on the available evidence, the GNAS c.565_568delGACT (p.D189Mfs*14) alteration is classified as pathogenic for pseudohypoparathyroidism and pseudopseudohypoparathyroidism; however, it is unlikely to be causative of McCune-Albright syndrome. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in the heterozygous state in multiple individuals with pseudohypoparathyroidism or pseudopseudohypoparathyroidism (Chang, 2022; Goode, 2022; Itoh, 2022; Stembridge, 2021; Mendes, 2021; Ozaki, 2021; Crane, 2020; Snanoudj, 2020; Del Monte, 2019; Miyakawa, 2019; Salemi, 2018; Inta, 2014; Schrander, 2014; Elli, 2013; Lebrun, 2010; Adegbite, 2008; Shore, 2002; Weinstein, 1992) Based on the available evidence, this alteration is classified as pathogenic. -

Pseudohypoparathyroidism type I A Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Genetics of Obesity Study, University of Cambridge

Jun 01, 2020

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Progressive osseous heteroplasia;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C3494506:Pseudohypoparathyroidism type I A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 15, 2022

The c.565_568del p.(Asp189MetfsTer14) variant identified in the GNAS gene has previously been reported in many individuals with Progressive osseous heteroplasia as well as pseudohypoparathyroidism type 1a [PMID: 23796510, 11784876, 20427508, 30729047] and it has been deposited in ClinVar [ClinVarID: 15938] as Pathogenic. The c.565_568del variant is observed in 1 allele (0.0003% MAF with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.565_568del p.(Asp189MetfsTer14) variant in the GNAS gene is located in exon 7 of this 13-exon gene, predicted to incorporate a premature termination codon (p.(Asp189MetfsTer14)), and is expected to resultin loss-of-function either through protein truncation or nonsense-mediated mRNA decay. Multiple loss-of-function variants that are downstream to the c.565_568del variant have been reported in the literature [PMID: 20427508, 31886927] in individuals with Progressive osseous heteroplasia or pseudohypoparathyroidism type 1a. Based on available evidence this c.565_568del p.(Asp189MetfsTer14) variant identified in GNAS is classified as Pathogenic. -

Pseudopseudohypoparathyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2008

- -

Disorders of GNAS Inactivation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 04, 2023

The GNAS c.565_568del (p.Asp189MetfsTer14) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been identified in multiple individuals with phenotypes consistent with disorders of GNAS inactivation (PMID: 23796510; 35296306). The c.565_568del variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies conducted in patient cells demonstrated that this variant leads to reduced mRNA expression (PMID: 1505964). This variant has been classified as pathogenic by multiple submitters in ClinVar. Based on the available evidence, the c.565_568del variant is classified as pathogenic for disorders of GNAS inactivation. -

GNAS-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 24, 2023

The GNAS c.565_568delGACT variant is predicted to result in a frameshift and premature protein termination (p.Asp189Metfs*14). This variant has been reported in many unrelated individuals with either progressive osseous heteroplasia (POH) or pseudohypoparathyroidism type 1a (PHP1a) (Lebrun et al. 2010. PubMed ID: 20427508; Salemi et al. 2018. PubMed ID: 29059381; Inta et al. 2014. PubMed ID: 24481334). In several of these patients this variant was found to occur de novo (Lebrun et al. 2010. PubMed ID: 20427508; Crane et al. 2019. PubMed ID: 31793173). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in GNAS are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587776829; hg19: chr20-57484248;