Submissions for variant NM_000516.7(GNAS):c.137T>G (p.Leu46Arg)

dbSNP: rs1600976255

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Johns Hopkins Genomics, Johns Hopkins University	RCV000850178	SCV000992373	uncertain significance	Pseudohypoparathyroidism	2019-06-18	criteria provided, single submitter	clinical testing	This GNAS variant is absent from large population datasets and has not been reported in ClinVar or the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be probably damaging/damaging, and the leucine residue at this position is poorly evolutionarily conserved across the species assessed. Bioinformatic analysis predicts that this synonymous variant would not affect normal exon 1 splicing, although this has not been confirmed experimentally to our knowledge. The clinical significance of c.137T>G is uncertain at this time.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005054277	SCV005688718	likely pathogenic	Pseudohypoparathyroidism type 1C; Pseudohypoparathyroidism type 1B; Pseudopseudohypoparathyroidism; Progressive osseous heteroplasia; Pseudohypoparathyroidism type I A	2024-01-03	criteria provided, single submitter	clinical testing	The GNAS c.137T>G (p.Leu46Arg) variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GNAS function. This variant has been reported in the ClinVar database as a germline variant of uncertain significance for pseudohypoparathyroidism type IA by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.