Submissions for variant NM_001009944.3(PKD1):c.7077G>C (p.Arg2359=)

gnomAD frequency: 0.01868  dbSNP: rs4018162

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999839	SCV000604739	benign	Polycystic kidney disease, adult type	2020-01-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712643	SCV000843161	benign	not provided	2017-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000712643	SCV001830901	likely benign	not provided	2021-05-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17574468)
Fulgent Genetics, Fulgent Genetics	RCV000999839	SCV002795873	benign	Polycystic kidney disease, adult type	2022-04-30	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000712643	SCV005217065	likely benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003891876	SCV000305771	benign	PKD1-related disorder	2019-10-15	no assertion criteria provided	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292518	SCV001480676	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg2359= variant was identified in 3 of 164 proband chromosomes (frequency: 0.018) from individuals or families with ADPKD and was not identified in 342 control chromosomes from healthy individuals (Garcia-Gonzalez, 2007). The variant was also identified in dbSNP (ID: rs4018162) as “With Benign allele”, Clinvitae and ClinVar (as benign by PreventionGenetics) and ADPKD Mutation Database (as likely benign). This variant was identified in the 1000 Genomes Project in 106 of 5008 chromosomes (frequency: 0.021), the genome Aggregation Database (beta, October 19th 2016) in 950 (19 homozygous) of 222394 chromosomes (freq. 0.0042), the Exome Aggregation Consortium database (August 8th 2016) in 253 of 85618 chromosomes (freq. 0.003) in the following populations: African in 91 of 4854 chromosomes (freq. 0.018), South Asian in 84 of 13972 chromosomes (freq. 0.006), East Asian in 25 of 6664 chromosomes (freq. 0.0037), Latino in 22 of 8658 chromosomes (freq. 0.0025), European in 30 of 47220 chromosomes (freq. 0.0006), and Finnish in 1 of 3634 chromosomes (freq. 0.000275), but was not seen in other populations, increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. In addition the variant was identified with a co-occurring pathogenic PKD1 variant (c.7863+1delG) by our laboratory in a patient with ADPKD, increasing the likelihood that the p.Arg2359= variant does not have clinical significance. This variant was not identified in GeneInsight COGR, MutDB, PKD1-LOVD, PKD1-LOVD 3.0, and the NHLBI GO Exome Sequencing Project databases. The p.Arg2359= 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. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.