Submissions for variant NM_001009944.3(PKD1):c.11258G>A (p.Arg3753Gln)

dbSNP: rs1555446330

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001552580	SCV000604790	likely pathogenic	not provided	2024-10-16	criteria provided, single submitter	clinical testing	The PKD1 c.11758G>A; p.Arg3753Gln variant (rs1555446330, ClinVar Variation ID: 440120) has been reported in multiple individuals diagnosed with autosomal dominant polycystic kidney disease (ADPKD; Benson 2021, Carrera 2016, Cornec-Le Gall 2013, Domingo-Gallego 2022, Kim 2019, Rossetti 2007, Stekrova 2009). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.11257C>T, p.Arg3753Trp) has been reported in multiple individuals with ADPKD, and is considered likely pathogenic (Audrezet 2012, Cornec-Le Gall 2013, Rossetti 2007). Computational analyses predict that this variant is deleterious (REVEL: 0.700). Based on available information, including its prevalence in affected individuals, this variant is considered to be likely pathogenic. References: Audrezet M et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012; 33(8):1239-50. PMID: 22508176. Benson KA et al. The genetic landscape of polycystic kidney disease in Ireland. Eur J Hum Genet. 2021 May;29(5):827-838. PMID: 33454723. Carrera P et al. Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Sci Rep. 2016 Aug 8;6:30850. PMID: 27499327. Cornec-Le Gall E et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013; 24(6):1006-13. PMID: 23431072. Domingo-Gallego A et al. Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. Nephrol Dial Transplant. 2022 Mar 25;37(4):687-696. PMID: 33532864. Kim H et al. Genetic Characteristics of Korean Patients with Autosomal Dominant Polycystic Kidney Disease by Targeted Exome Sequencing. Sci Rep. 2019 Nov 18;9(1):16952. PMID: 31740684. Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007; 18(7):2143-60. PMID: 17582161. Jayasinghe K et al. Clinical impact of genomic testing in patients with suspected monogenic kidney disease. Genet Med. 2021 Jan;23(1):183-191. PMID: 32939031. Stekrova J et al. New mutations in the PKD1 gene in Czech population with autosomal dominant polycystic kidney disease. BMC Med Genet. 2009 Aug 17;10:78. PMID: 19686598.
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000507238	SCV001251224	uncertain significance	Polycystic kidney disease, adult type	2020-02-05	criteria provided, single submitter	research	PM2, PP3, PP4, PP5
Molecular Biology Laboratory, Fundació Puigvert	RCV000507238	SCV001425143	likely pathogenic	Polycystic kidney disease, adult type	2020-02-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000507238	SCV001427203	pathogenic	Polycystic kidney disease, adult type	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated polycystin domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg3753Gly) and p.(Arg3753Trp) have been classified as likely pathogenic and pathogenic in ClinVar, and p.(Arg3753Trp) has been observed in individuals with polycystic kidney disease (PMID: 26453610, 17582161, 22508176). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar and LOVD, and has been observed in multiple unrelated heterozygous individuals with polycystic kidney disease (PMID: 17582161, 27499327, 26453610, 22508176, 19686598, 33532864). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001552580	SCV001773288	likely pathogenic	not provided	2024-12-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31740684, 24907393, 10729710, 23431072, 19686598, 22508176, 17582161, 27499327, 33454723, 32939031, 33532864, 36938073)
PreventionGenetics, part of Exact Sciences	RCV003392341	SCV004120071	pathogenic	PKD1-related disorder	2023-08-19	criteria provided, single submitter	clinical testing	The PKD1 c.11258G>A variant is predicted to result in the amino acid substitution p.Arg3753Gln. Multiple different substitutions at the same codon, including p.Arg3753Gln, have been reported to be causative for autosomal dominant polycystic kidney disease (ADPKD) (see p.Arg3753Gln for example at at Rossetti et al. 2012. PubMed ID: 22383692 and Suppl. Table 3 of Benson et al. 2021. PubMed ID: 33454723; https://pkdb.mayo.edu/; Human Gene Mutation Database - HGMD). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.