Submissions for variant NM_002711.4(PPP1R3A):c.1985_1986del (p.Gln662fs)

gnomAD frequency: 0.00279  dbSNP: rs527638422

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503729	SCV000596570	uncertain significance	not specified	2016-05-11	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174456	SCV001337595	uncertain significance	Monogenic diabetes	2018-11-21	criteria provided, single submitter	research	ACMG criteria: PVS1 (not sure whether frameshift, not sure whether LOF of PPP1R3A is a known mechanism for disease since there is only one report and in this report the deletion could be a modifier ) Variant reported in PMID 12118251: PPARG/PPP1R3A digenic inheritance; BS2 (3 homozygotes in gnomAD NFE)=VUS
Breakthrough Genomics, Breakthrough Genomics	RCV001358246	SCV005195597	uncertain significance	not provided		criteria provided, single submitter	not provided
OMIM	RCV002280818	SCV000029462	pathogenic	Insulin resistance, severe, digenic	2002-08-01	no assertion criteria provided	literature only
OMIM	RCV002280817	SCV000029463	pathogenic	TYPE 2 DIABETES MELLITUS, DIGENIC	2002-08-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358246	SCV001553923	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PPP1R3A p.Gln662Argfs*7 variant was not identified in the literature but was identified in dbSNP (ID: rs527638422), ClinVar (classified as a VUS by Genetic Services Laboratory, University of Chicago), Cosmic and LOVD 3.0 (classified as a VUS). The variant was also identified in control databases in 647 of 282108 chromosomes (3 homozygous) at a frequency of 0.002293 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 563 of 128528 chromosomes (freq: 0.00438), Other in 12 of 7206 chromosomes (freq: 0.001665), European (Finnish) in 34 of 25120 chromosomes (freq: 0.001354), African in 24 of 24962 chromosomes (freq: 0.000962) and Latino in 14 of 35390 chromosomes (freq: 0.000396), but was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. The c.1985_1986del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 662 and leads to a premature stop codon 7 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the PPP1R3A gene are not a known mechanism of disease. 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.