Submissions for variant NM_001009944.3(PKD1):c.3935G>A (p.Arg1312Gln)

gnomAD frequency: 0.00924  dbSNP: rs142129358

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000037	SCV000604781	benign	Polycystic kidney disease, adult type	2019-12-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000507077	SCV001144979	benign	not provided	2018-12-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000507077	SCV001859954	benign	not provided	2020-02-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001000037	SCV002798631	likely benign	Polycystic kidney disease, adult type	2021-11-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000507077	SCV005290723	benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292509	SCV001480642	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg1312Gln variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) 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: rs142129358) as “N/A”, the ADPKD Mutation Database (classified as likely neutral), 1000 Genomes Project in 43 of 5000 chromosomes (frequency: 0.009), the NHLBI GO Exome Sequencing Project in 117 of 4364 African American alleles, the genome Aggregation Database (beta, October 19th 2016) in 776 (12 homozygous) of 271038 chromosomes (freq. 0.003), the Exome Aggregation Consortium database (August 8th 2016) in 304 (3 homozygous) of 113380 chromosomes (freq. 0.003) in the following populations: African in 288 of 8892 chromosomes (freq. 0.03), Latino in 12 of 11216 chromosomes (freq. 0.001), European in 4 of 62116 chromosomes (freq. 0.0001), but was not seen in Asian, Finnish, and Other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was not found in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD and PKD1-LOVD 3.0. The p.Arg1312 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the variant was identified with a co-occurring pathogenic PKD1 variant (L3343fsX), increasing the likelihood that the p.Arg1312Gln variant does not have clinical significance (Garcia-Gonzalez 2007). In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003925506	SCV004740335	benign	PKD1-related disorder	2020-04-25	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).