Submissions for variant NM_000516.7(GNAS):c.565_568del (p.Asp189fs)

dbSNP: rs587776829

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678707	SCV000804871	pathogenic	not specified	2017-12-20	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000017300	SCV000992358	pathogenic	Pseudohypoparathyroidism	2019-10-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196108	SCV001366579	pathogenic	Pseudohypoparathyroidism type 1B	2019-02-24	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM1,PM2,PP5.
Genetics of Obesity Study, University of Cambridge	RCV001731307	SCV001573812	pathogenic	Pseudohypoparathyroidism type I A	2020-06-01	criteria provided, single submitter	research
Invitae	RCV001851884	SCV002232612	pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001851884	SCV002499789	pathogenic	not provided	2022-04-06	criteria provided, single submitter	clinical testing	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)
Fulgent Genetics, Fulgent Genetics	RCV002496387	SCV002806191	pathogenic	McCune-Albright syndrome; Pseudohypoparathyroidism type 1C; Pseudohypoparathyroidism type 1B; Pseudopseudohypoparathyroidism; Progressive osseous heteroplasia; Pituitary adenoma 3, multiple types; ACTH-independent macronodular adrenal hyperplasia 1; Pseudohypoparathyroidism type I A	2022-04-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162254	SCV003887548	pathogenic	Inborn genetic diseases	2023-01-25	criteria provided, single submitter	clinical testing	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. 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.
New York Genome Center	RCV003227604	SCV003925361	pathogenic	Pseudohypoparathyroidism type 1C; Pseudohypoparathyroidism type 1B; Progressive osseous heteroplasia; Pseudohypoparathyroidism type I A	2022-04-15	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV003389234	SCV004101287	pathogenic	Disorders of GNAS Inactivation	2023-08-04	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003934835	SCV004749516	pathogenic	GNAS-related condition	2023-12-24	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000017300	SCV000037572	pathogenic	Pseudohypoparathyroidism	2008-07-15	no assertion criteria provided	literature only
OMIM	RCV000017301	SCV000037573	pathogenic	Progressive osseous heteroplasia	2008-07-15	no assertion criteria provided	literature only
OMIM	RCV000017302	SCV000037574	pathogenic	Pseudopseudohypoparathyroidism	2008-07-15	no assertion criteria provided	literature only
GeneReviews	RCV000017301	SCV000611857	not provided	Progressive osseous heteroplasia		no assertion provided	literature only