Submissions for variant NM_016953.4(PDE11A):c.171del (p.Thr58fs)

gnomAD frequency: 0.00056  dbSNP: rs529789124

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000903265	SCV000245648	uncertain significance	not provided	2016-11-28	criteria provided, single submitter	clinical testing	The p.Thr58ProfsX41 variant in PDE11A has been reported in 1 individual with adrenocortical hyperplasia and Cushing syndrome, and segregated with disease in 1 parent with hypertension, obesity, and bilaterally enlarged adrenal glands (Horvath 2006). This variant has also been reported in 1 individual with acromegaly (Peverelli 2009) and in 3 individuals with Carney complex who also carried PRKAR1A variants, and was considered to be a possible modifier of disease in these individuals (Libe 2011). The p.Thr58ProfsX41 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 58 and leads to a premature termination codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Several loss-of-function PDE11A variants have been described in individuals with Cushing syndrome and with adrenal hyperplasia with established loss-of-heterozygosity in somatic tissue (Horvath 2006, Carney 2010, Libe 2011). However, this variant has been identified in 4% (647/16342; 17 homozygotes) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org) calling into question the validity of a pathogenic interpretation and leaving the clinical significance of the p.Thr58ProfsX41 variant as uncertain.
GeneDx	RCV000485692	SCV000565363	benign	not specified	2016-07-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000903265	SCV001047723	benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001258305	SCV001435254	likely benign	Bardet-Biedl syndrome 16		criteria provided, single submitter	research	The c.171delT variant in PDE11A has been identified in 6 individuals with possible adrenocortical hyperplasia (PMID: 16767104, 19671705, 20351491, 21047926), and has been identified in >3% of South Asian chromosomes and 18 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for adrenocortical hyperplasia.
CeGaT Center for Human Genetics Tuebingen	RCV000903265	SCV004150159	benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PDE11A: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003937676	SCV004749853	benign	PDE11A-related disorder	2020-12-11	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000190613	SCV004810127	likely benign	Pigmented nodular adrenocortical disease, primary, 2	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000190613	SCV000025787	uncertain significance	Pigmented nodular adrenocortical disease, primary, 2	2006-07-01	no assertion criteria provided	literature only