ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.8293C>T (p.Arg2765Cys) (rs144979397)

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Total submissions: 8
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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 uncertain significance Polycystic kidney disease, adult type 2019-05-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000507033 SCV001145016 benign not provided 2019-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000507033 SCV001875158 uncertain significance not provided 2021-03-30 criteria provided, single submitter clinical testing 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); 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); 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: 33639313, 27499327, 22383692, 11115377, 11857740, 26139440, 24374109, 29801666, 25920554, 19165178, 24907393)
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).
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001701626 SCV001931534 benign not specified no assertion criteria provided clinical testing

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