ClinVar Miner

Submissions for variant NM_000516.7(GNAS):c.348dup (p.Val117fs)

dbSNP: rs2090848106
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001090864 SCV001246624 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001090864 SCV002065894 pathogenic not provided 2021-11-29 criteria provided, single submitter clinical testing DNA sequence analysis of the GNAS gene demonstrated a single base pair duplication in exon 5, c.348dup. This duplication results in an amino acid frameshift and creates a premature stop codon 23 amino acids downstream of the change, p.Val117Argfs*23. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated GNAS protein with potentially abnormal function. The c.348dup sequence change has not been described in population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in individuals with GNAS-related disorders including three individuals with a diagnosis of pseudohypoparathyroidism 1A (confirmed de novo in two cases) and one individual with a diagnosis of progressive osseous heteroplasia (paternally inherited) (PMID: 12621129, 20689139, 117848760. This pathogenic sequence change is the most likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively.
3billion RCV002250726 SCV002520970 pathogenic Pseudohypoparathyroidism type I A 2022-05-22 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: 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. The variant has been reported to be associated with GNAS related disorder (ClinVar ID: VCV000871093). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV002489729 SCV002778605 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 2022-03-18 criteria provided, single submitter clinical testing
Invitae RCV001090864 SCV003443820 pathogenic not provided 2023-05-23 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: 871093). This premature translational stop signal has been observed in individual(s) with clinical features of GNAS-related conditions (PMID: 12621129, 31886927). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val117Argfs*23) 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).
GeneDx RCV001090864 SCV003805967 pathogenic not provided 2022-08-26 criteria provided, single submitter clinical testing 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31886927, 12621129)

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