ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.9829C>T (p.Arg3277Cys) (rs148812376)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497386 SCV000589517 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing The R3277C variant in the PKD1 gene has been reported previously in the heterozygous, homozygous, and compound heterozygous state associated with variable severity of polycystic kidney disease (Rossetti et al., 2009; Audrézet et al., 2016). The R3277C variant was identified through four generations of a consanguineous family; two siblings homozygous for the R3277C variant developed end stage renal disease at age 62 and 75 whereas 6 additional heterozygous family members had few renal cysts (Rossetti et al., 2009). The R3277C variant has also been seen in trans with another disease causing variant in association with in utero polycystic kidney disease (Rossetti et al., 2009; Audrézet et al., 2016). In addition, a knockin mouse model demonstrated mice that were heterozygous for the 3277C variant had no clinical features, homozygous mice developed gradual cystogenesis, and mice that were compound heterozygous for the 3277C variant and the null allele had rapidly progressive disease (Hopp et al., 2012). The R3277C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R3277Cvariant is a non-conservative amino acid substitution, which occurs at a position that is conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R3277C as a pathogenic variant.
Broad Institute Rare Disease Group,Broad Institute RCV000192215 SCV001164388 likely pathogenic Polycystic kidney disease, adult type 2018-12-03 criteria provided, single submitter research The heterozygous p.Arg3277Cys variant in PKD1 was identified by our study in one individual with polycystic kidney disease and their unaffected parent. This variant has been seen in 0.04351% (36/82736) of European (non-Finnish) chromosomes. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg3277Cys variant in PKD1 has been reported in ten individuals in one cosanguineous family with polycystic kidney disease and segregated with disease in eight affected relatives with varying expressivity. The disease status of the remaining two relatives was unknown (PMID: 19165178). This variant was also reported in the compound heterozygous state (with a pathogenic variant in one case) in two unrelated individuals with polycystic kidney disease (PMID: 19165178, 26139440). The presence of this variant in combination with a reported pathogenic variant and in an individual with polycystic kidney disease increases the likelihood that the p.Arg3277Cys variant is pathogenic. Animal models in mice have shown that this variant in the homozygous and compound heterozygous state with a null variant does cause a phenotype matching polycystic kidney disease (PMID: 23064367). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP3, PP1_Moderate, PM3, PS3 (Richards 2015).
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000192215 SCV001427194 pathogenic Polycystic kidney disease, adult type 2019-03-22 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_001009944.2(PKD1):c.9829C>T, has been identified in exon 29 of 46 of the PKD1 gene. The variant is predicted to result in a major amino acid change from arginine to cysteine at position 3277 of the protein (NP_001009944.2(PKD1):p.(Arg3277Cys)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.02% (44 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic in multiple families with polycystic kidney disease (ClinVar). The hypomorphic nature of this variant also means it can be associated with severe or very early onset disease when in biallelic form (PKD database, Cornec-Le Gall, E. et al (2018), Rossetti, S. et al. (2009), Audrezet MP. et al. (2016), Carrera, P. et al. (2016)). Functional analyses demonstrated p.Arg3277Cys affects PC-1 cleavage in addition to protein folding and trafficking. In addition, a knock-in mouse model has been shown to result in rapidly progressive disease when present in compound heterozygous form (Hopp, K. et al. (2012)). Subsequent analysis of parental samples indicated this variant was paternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Molecular Genetics of Inherited Kidney Disorders Laboratory,Garvan Institute of Medical Research RCV001254214 SCV001430283 uncertain significance Polycystic kidney disease, autosomal dominant 2019-01-01 criteria provided, single submitter research
GeneReviews RCV000192215 SCV000223894 pathogenic Polycystic kidney disease, adult type 2015-06-11 no assertion criteria provided literature only
Gharavi Laboratory,Columbia University RCV000497386 SCV000920751 likely benign not provided 2018-09-16 no assertion criteria provided research

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