Submissions for variant NM_016953.4(PDE11A):c.919C>T (p.Arg307Ter)

gnomAD frequency: 0.00292  dbSNP: rs76308115

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000950090	SCV000514083	likely benign	not provided	2019-08-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18559625, 20351491, 25525159, 23771924, 26820475, 21047926, 16767104, 29495593, 30262796, 32098292)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000950090	SCV001096371	likely benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251878	SCV002523832	uncertain significance	See cases	2020-11-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, BS1
CeGaT Center for Human Genetics Tuebingen	RCV000950090	SCV004150158	benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PDE11A: BS1, BS2
OMIM	RCV000005604	SCV000025786	pathogenic	Pigmented nodular adrenocortical disease, primary, 2	2006-07-01	flagged submission	literature only
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000005604	SCV000746542	pathogenic	Pigmented nodular adrenocortical disease, primary, 2	2017-12-03	flagged submission	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000950090	SCV001552503	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PDE11A p.Arg57X variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs76308115), Cosmic (FATHMM prediction score of neutral) and ClinVar (classified as likely benign by GeneDx and pathogenic by Genomic Research Center, Shahid Beheshti University of Medical Sciences for pigmented nodular adrenocortical disease, 2). The variant was identified in control databases in 849 of 281828 chromosomes (5 homozygous) at a frequency of 0.003012 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 613 of 128514 chromosomes (freq: 0.00477), Other in 26 of 7184 chromosomes (freq: 0.003619), European (Finnish) in 73 of 25042 chromosomes (freq: 0.002915), Ashkenazi Jewish in 25 of 10350 chromosomes (freq: 0.002415), South Asian in 41 of 30580 chromosomes (freq: 0.001341), Latino in 43 of 35376 chromosomes (freq: 0.001216) and African in 28 of 24956 chromosomes (freq: 0.001122); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg57X variant leads to a premature stop codon at position 57 which is predicted to lead to a truncated or absent protein and loss of function. Other loss of function variants (c.919C>T, p.R317X) have been identified in the PDE11A gene as causal for Cushing Syndrome and ovarian cysts (Hovarth_2006_PMID: 16767104), indicating that stop gain variants in the PDE11A gene are disease-causing. Further, MutationTaster predicts the variant to be disease causing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.