Submissions for variant NM_001009944.3(PKD1):c.8293C>T (p.Arg2765Cys)

gnomAD frequency: 0.00495  dbSNP: rs144979397

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000162091	SCV000604787	uncertain significance	Polycystic kidney disease, adult type	2018-09-22	criteria provided, single submitter	clinical testing	The PKD1 c.8293C>T; p.Arg2765Cys variant (rs144979397) is reported in the literature in the compound heterozygous state with a truncating PKD1 variant on the opposite chromosome in multiple individuals with autosomal polycystic kidney disease, or in the heterozygous state in fetuses affected with in-utero polycystic kidney disease, suggesting that this is a hypomorphic allele (McCluskey 2002, Rossetti 2001, Rossetti 2009, Rossetti 2012). This variant is listed in ClinVar (Variation ID: 183257), and is found in the general population with an allele frequency of 0.47% (1299/278,546 alleles, including 9 homozygotes) in the Genome Aggregation Database. The arginine at residue 2765 is moderately conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious. Due to the conflicting information regarding this variant, its clinical significance could not be determined with certainty. References: McCluskey M et al. Mutation detection in the duplicated region of the polycystic kidney disease 1 (PKD1) gene in PKD1-linked Australian families. Hum Mutat. 2002; 19(3):240-50. Rossetti S et al. Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet. 2001; 68(1):46-63. Rossetti S et al. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int. 2009; 75(8):848-55. Rossetti S et al. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012 May;23(5):915-33.
Mendelics	RCV000162091	SCV001139779	benign	Polycystic kidney disease, adult type	2023-08-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000507033	SCV001145016	benign	not provided	2019-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000507033	SCV001875158	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing	Reported in unrelated individuals, with one or more additional PKD1 variants, with polycystic kidney disease (Rossetti et al., 2012; Audrezet et al., 2016; Carrera et al., 2016; Cnossen et al., 2016; Bullich et al., 2018); Reported previously in multiple individuals with polycystic kidney disease (PKD), including two unrelated individuals with in utero presentation, who also harbored a loss-of-function PKD1 variant in trans with R2765C, leading the authors to postulate that R2765C may be a hypomorphic allele (Tan et al., 2014; Rossetti et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; R2765C had no identifiable impact on pre-mRNA splicing as a mechanism of disease in a minigene assay (Gonzalez-Paredes et al., 2014); This variant is associated with the following publications: (PMID: 24907393, 19165178, 29801666, 26139440, 11857740, 11115377, 22383692, 27499327, 33639313, 33226606, 33454723, 25920554, 24374109)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000162091	SCV002557518	likely benign	Polycystic kidney disease, adult type	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. 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 cysteine. (I) 0251 - This variant is heterozygous. (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (37 heterozygotes, 0 homozygotes). (I) 0308 - Population frequency for this variant is out of keeping with known incidence of polycystic kidney disease 1 (MIM#173900). (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated REJ domain (UniProt). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.(Arg2765His)) has been reported as a VUS and as a polymorphism (ClinVar, PMID: 26632257, PMID: 27499327). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been recently reported as benign, a VUS and as a likely pathogenic hypomorphic allele, and is commonly observed in multiple individuals with PKD who had additional causative variants in the PKD1 and PKD2 genes (ClinVar, pkdb.mayo.edu, PMID: 27499327, PMID: 33639313, PMID: 33226606). (I) 1010 - Functional evidence for this variant is inconclusive. An individual with this variant and two additional pathogenic variants in the PKD1 and PKD2 genes, demonstrated reduced TRPP2 expression but no change in PC1 (PMID: 31514750). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000507033	SCV002585538	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BS2
Ambry Genetics	RCV002516435	SCV003688964	likely benign	Inborn genetic diseases	2022-12-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235079	SCV003934671	likely benign	not specified	2023-05-26	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.8293C>T (p.Arg2765Cys) results in a non-conservative amino acid change located in the REJ domain (IPR014010) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0047 in 247274 control chromosomes (gnomAD), predominantly at a frequency of 0.0087 within the Non-Finnish European subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 17-fold of the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing Polycystic Kidney Disease 1 phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.8293C>T has been reported in the literature in individuals affected with Polycystic Kidney Disease 1 (Nielsen_2021, Rossetti_2009, Vaisitti_2021, Senum_2022). In some individuals, the variant was found with other (likely) pathogenic PKD1 variants in trans or with pathogenic IFT140 variants, suggesting an alternate mechanism for disease, although it has also been suggested that the variant has a hypomorphic effect (Rossetti_2009). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney Disease 1. 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: 19165178, 33226606, 33639313, 34890546). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and reported the variant with conflicting assessments (benign/likely benign n=4, likely pathogenic n=1, uncertain significance n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV000162091	SCV000212090	not provided	Polycystic kidney disease, adult type		no assertion provided	not provided
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000162091	SCV001192663	likely pathogenic	Polycystic kidney disease, adult type	2019-11-26	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292109	SCV001480941	likely pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg2765Cys variant was identified in 16 of 1980 proband chromosomes (frequency: 0.008) from individuals or families with Autosomal Dominant PKD (Borras 2017, Carrera 2016, Cnossen 2016, McCluskey 2002, Rossetti 2001, Rossetti 2012). The variant was also identified in dbSNP (ID: rs144979397) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by ARUP, and classification not provided by Radboud University Medical Center), LOVD 3.0, ADPKD Mutation Database (classified as likely hypomorphic), and PKD1-LOVD (1x co-occurring with PKD2 variant IVS4+1G>A, PKD1 c.10043G>A). The variant was also identified by our laboratory in 6 individuals with PKD. Our laboratory found the variant co-occuring with a pathogenic PKD1 variant (p.Arg2402*), and the variant was also reported in the literature as co-occurring with 4 more pathogenic PKD1 and PKD2 variants (Borras 2017, Carrera 2016, Rossetti 2012). Rossetti (2012) studied one patient diagnosed in childhood who was found to be a compound heterozygote for the PKD1 variants p.Arg2765Cys and p.Arg3105Trp. In their study, the pattern of inheritance suggested that both incompletely penetrant variants are required for polycystic kidney disease development and that a single variant can be associated with rare cyst development (Rossetti 2012). The variant was reported as hypomorphic in several papers (Cnossen 2016, Rossetti 2009 and Rossetti 2012). However, Tan (2014) and McCluskey (2002) classified the variant as probably neutral. The variant was identified in control databases in 1251 of 274850 chromosomes (8 homozygous) at a frequency of 0.005 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 37 of 23696 chromosomes (freq: 0.001561), Other in 16 of 6408 chromosomes (freq: 0.002497), Latino in 71 of 34396 chromosomes (freq: 0.002064), European (Non-Finnish) in 1053 of 124928 chromosomes (freq: 0.008429), Ashkenazi Jewish in 11 of 10076 chromosomes (freq: 0.001092), Finnish in 57 of 25744 chromosomes (freq: 0.002214), and South Asian in 6 of 30770 chromosomes (freq: 0.000195), while the variant was not observed in the East Asian population. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. Although the p.Arg2765 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cysteine variant may impact the protein. 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 pathogenic role for this variant. In isolation this variant is unlikely to cause disease however with another hypomorphic variant or a pathogenic variant in PKD1 the c.8293C>T variant is likely to influence disease progression. This variant is classified as likely pathogenic (hypomorphic).
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000507033	SCV001974888	likely benign	not provided		no assertion criteria provided	clinical testing