Submissions for variant NM_001377265.1(MAPT):c.889C>A (p.Arg297Ser)

gnomAD frequency: 0.00038  dbSNP: rs150983093

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791003	SCV000930266	uncertain significance	Frontotemporal dementia	2019-04-27	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791004	SCV000930267	uncertain significance	Pick disease	2019-04-27	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791005	SCV000930268	uncertain significance	Multiple system atrophy	2019-04-27	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791006	SCV000930269	uncertain significance	Progressive supranuclear ophthalmoplegia	2019-04-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001354954	SCV001549688	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MAPT p.R222S variant was identified in the literature in a patient with early onset frontotemporal lobar degeneration who also had two PPT1 variants (Jeung_2015_PMID:29595823). The variant was identified in dbSNP (ID: rs150983093) and ClinVar (classified as uncertain significance by Genomic Research Center, Shahid Beheshti University of Medical Sciences). The variant was identified in control databases in 80 of 274120 chromosomes at a frequency of 0.0002918 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 22 of 24108 chromosomes (freq: 0.000913), Other in 5 of 7046 chromosomes (freq: 0.00071), Latino in 24 of 35096 chromosomes (freq: 0.000684) and European (non-Finnish) in 29 of 123262 chromosomes (freq: 0.000235), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.R222 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001354954	SCV001740683	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001354954	SCV001970859	likely benign	not provided		no assertion criteria provided	clinical testing