Submissions for variant NM_001009944.3(PKD1):c.10304G>A (p.Arg3435Gln)

gnomAD frequency: 0.00328  dbSNP: rs140189010

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003891862	SCV000305663	benign	PKD1-related condition	2020-09-03	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).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000442857	SCV000511047	likely benign	not provided	2016-12-05	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002095	SCV001159942	likely benign	Polycystic kidney disease, adult type	2019-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000442857	SCV001788409	likely benign	not provided	2020-10-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27567292)
Fulgent Genetics, Fulgent Genetics	RCV001002095	SCV002813632	likely benign	Polycystic kidney disease, adult type	2021-12-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000442857	SCV004129915	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292524	SCV001480682	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg3435Gln variant was identified in 6 of 460 proband chromosomes (frequency: 0.01) from individuals with autosomal dominant polycystic kidney disease (Rossetti 2012). The variant was also identified in dbSNP (rs140189010) as “with likely benign allele”, ClinVar (interpreted as "likely benign" by PreventionGenetics and 1 other submitter), LOVD 3.0 and ADPKD Mutation Database. The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 693 of 271,186 chromosomes at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 25 of 23,576 chromosomes (freq: 0.001), Other in 11 of 6390 chromosomes (freq: 0.002), Latino in 19 of 34,358 chromosomes (freq: 0.0005), European in 609 of 124,992 chromosomes (freq: 0.005), Ashkenazi Jewish in 2 of 10,044 chromosomes (freq: 0.0002), Finnish in 26 of 22,306 chromosomes (freq: 0.001) and South Asian in 1 of 30,740 chromosomes (freq: 0.00003); it was not observed in the East Asian population. The p.Arg3435 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.