Submissions for variant NM_001009944.3(PKD1):c.1710C>T (p.His570=)

gnomAD frequency: 0.00775  dbSNP: rs367983387

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003891865	SCV000305701	benign	PKD1-related condition	2019-06-20	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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000576550	SCV000604813	benign	Polycystic kidney disease, adult type	2020-04-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000576550	SCV000677399	benign	Polycystic kidney disease, adult type	2017-05-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000250167	SCV000700384	benign	not specified	2017-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001549967	SCV001770214	likely benign	not provided	2020-12-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000576550	SCV002811363	likely benign	Polycystic kidney disease, adult type	2021-09-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001549967	SCV004142907	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BP7, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292414	SCV001480843	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.His570His variant was identified in 8 of 860 proband chromosomes (frequency: 0.009) from individuals or families with ADPKD (Rossetti 2001, Rossetti 2002, Rossetti 2012, Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs367983387) as “NA”, Clinvitae (classified as variant of unknown significance by Emory Genetics), and in the ADPKD Mutation Database (classification likely neutral); in the 1000 Genomes Project in 17 of 5000 chromosomes (frequency: 0.0034), in HAP-MAP: HAPMAP-EUR in 15 of 1006 chromosomes (frequency: 0.0149), HAPMAP-AMR in 1 of 694 chromosomes (frequency: 0.0014), HAPMAP-EAS in 1 of 1008 chromosomes (frequency: 0.001), NHLBI GO Exome Sequencing Project (ESP) in 40 of 8462 (frequency: 0.0047) European American, and in 3 of 4308 (frequency: 0.0007) African American alleles. The variant was also identified in the Exome Aggregation Consortium database (March 14, 2016) in 19 of 130 chromosomes (frequency: 0.1462) from a population of European (Finnish) individuals, in 164 (2 homozygous) of 7450 chromosomes (frequency: 0.02201) from a population of European (Non-Finnish) individuals, in 34 of 8056 chromosomes (frequency: 0.0042) from a population of South Asians, and in 3 of 1762 chromosomes (frequency: 0.0017) from a population of African individuals, increasing the likelihood this could be a low frequency benign variant. The variant was not seen in the East Asian, Other or Latino poulations. The variant was identified by our laboratory in a patient with PKD with a co-occurring pathogenic PKD1 variant (c.8388T>G, p.Tyr2796X), increasing the likelihood that the p.His570His variant does not have clinical significance. The p.His570His variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.