Submissions for variant NM_000516.7(GNAS):c.34C>T (p.Gln12Ter)

dbSNP: rs797045046

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191090	SCV000245487	pathogenic	Pseudohypoparathyroidism; Pseudopseudohypoparathyroidism	2014-10-07	criteria provided, single submitter	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.
Ambry Genetics	RCV001265981	SCV001444153	pathogenic	Inborn genetic diseases	2018-03-22	criteria provided, single submitter	clinical testing
3billion	RCV002051824	SCV002318828	pathogenic	Pseudopseudohypoparathyroidism	2022-03-22	criteria provided, single submitter	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.
Johns Hopkins Genomics, Johns Hopkins University	RCV002051824	SCV002570266	pathogenic	Pseudopseudohypoparathyroidism	2022-04-06	criteria provided, single submitter	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.
Fulgent Genetics, Fulgent Genetics	RCV002503750	SCV002796490	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	2021-09-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417694	SCV004115020	pathogenic	GNAS-related condition	2023-02-03	criteria provided, single submitter	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.
Invitae	RCV003556238	SCV004298102	pathogenic	not provided	2023-05-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 209158). This premature translational stop signal has been observed in individual(s) with GNAS-related conditions (PMID: 11092390, 21525160, 23533243, 27703483, 29059381, 31886927, 33144682). This variant is not present in population databases (gnomAD no frequency). 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).