Submissions for variant NM_001009944.3(PKD1):c.11257C>T (p.Arg3753Trp)

dbSNP: rs1167476946

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000681771	SCV000927574	pathogenic	not provided	2018-03-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001283789	SCV001752845	pathogenic	Polycystic kidney disease, adult type	2021-06-30	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001283789	SCV005417980	pathogenic	Polycystic kidney disease, adult type		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PM6_Supporting+PP4+PP3_Moderate+PM5_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005407879	SCV006071966	pathogenic	PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease	2025-03-21	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.11257C>T (p.Arg3753Trp) results in a non-conservative amino acid change located in the Polycystin domain (IPR046791) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.11257C>T has been reported in the literature in individuals affected with Autosomal Dominant Polycystic Kidney Disease and one of the reported cases has been de novo for this variant (Kim_2000, Chang_2013, Xu_2018, Groopman_2019, Duan_2024). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23985799, 39019822, 30586318, 10729710, 29529603). ClinVar contains an entry for this variant (Variation ID: 562323). Based on the evidence outlined above, the variant was classified as pathogenic.
Gharavi Laboratory, Columbia University	RCV000681771	SCV000809232	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV001283789	SCV001469173	pathogenic	Polycystic kidney disease, adult type	2020-02-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291995	SCV001481006	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg3753Trp variant was identified in 8 of 2172 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD (Audrézet 2012, Chang 2013, Kinoshita 2016). The variant was assessed to be likely pathogenic using a newly developed software package that integrated seven databases (Kinoshita 2016). In two functional studies on a different nucleotide change at the same position, the synonomous variant (c.11257C>A, p.Arg3753Arg), induced a pre-mRNA splicing defect, generating a new donor splice site and incorporating incomplete exons (Claverie-Martin 2015 , Gonzalez-Paredes 2014). The variant was not identified in the ADPKD Mutation Database, but an alternate substitution at this codon (c.11258G>A, p.R3753Q) was identified as being highly likely pathogenic. The variant was also not identified in dbSNP, ClinVar, GeneInsight-COGR, LOVD 3.0, PKD1-LOVD, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Genome Aggregation Consortium (Feb 27 2017) control databases. The p.Arg3753Trp residue is conserved across mammals and other organisms, and four out of four computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 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 summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as uncertain significance.