Submissions for variant NM_001009944.3(PKD1):c.10529C>T (p.Thr3510Met)

gnomAD frequency: 0.00702  dbSNP: rs45478794

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000246477	SCV000305666	benign	not specified		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000677315	SCV000604704	benign	Polycystic kidney disease, adult type	2020-02-03	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000677315	SCV000803480	benign	Polycystic kidney disease, adult type	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Benign - Stand Alone, for Polycystic kidney disease 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254285	SCV001430251	likely benign	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
GeneDx	RCV001706301	SCV001834347	benign	not provided	2019-09-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32823016, 11558899, 11691639, 12007219, 18640754, 19686598, 28578020, 27499327, 26632257, 26722532, 18067079, 20981092, 22185115)
Breakthrough Genomics, Breakthrough Genomics	RCV001706301	SCV005217027	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291844	SCV000592845	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Thr3510Met variant was identified in 25 of 1248 proband chromosomes (frequency: 0.020) from Japanese, Chinese and Czech individuals or families with ADPKD, and was identified in 6 of 200 control chromosomes from healthy individuals (Mizoguchi 2001, Inoue 2002, Reed 2008, Rossetti 2001, Tsuchiya 2001, Yu 2011, Stekrova 2009). The variant was identified with a co-occurring pathogenic PKD1 variant (Q2142X), increasing the likelihood that the p.Thr3510Met variant does not have clinical significance (Yu 2011). The variant was also identified in dbSNP (ID: rs45478794) “With NA allele”, ADPKD Mutation Database (classification likely neutral), 1000 Genomes Project in 192 of 5013 chromosomes (frequency: 0.0383); HAP-MAP populations: SAS in 120 of 978 chromosomes (frequency: 0.1227)/EAS in 63 of 1008 chromosomes (frequency: 0.0625)/EUR in 8 of 1006 chromosomes (frequency: 0.008), in the NHLBI GO Exome Sequencing Project (ESP) in 56 of 8588 (frequency: 0.0065) European American and in 12 OF 4388 (frequency: 0.0027)African American alleles, and in all populations in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015): South Asian in 1466 (87 homozygous) of 130000 chromosomes (frequency: 0.1128), East Asian in 432 (11 homozygous) of 6452 chromosomes (frequency: 0.0067), Other in 15 of 600 chromosomes (frequency: 0.025), European (Non-Finnish) in 388 (2 homozygous) of 45098 chromosomes (frequency: 0.0086), European (Finnish) in 26 of 3626 chromosomes (frequency: 0.0071), Latino in 43 of 7878 chromosomes (frequency: 0.0054) and African in 18 (1 homozygous) of 6646 chromosomes (frequency: 0.0027), increasing the likelihood this could be a low frequency benign variant.The p.Thr3510Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.