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

gnomAD frequency: 0.00032  dbSNP: rs148812376

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497386	SCV000589517	likely pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	A knock-in mouse model demonstrated mice that were heterozygous for the R3277C variant had no clinical features, homozygous mice developed gradual cystogenesis, and mice that were compound heterozygous for the R3277C variant and a null allele had rapidly progressive disease (Hopp et al., 2012); 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: 30249452, 32457805, 28903946, 19165178, 23064367, 24907393, 29463793, 23431072, 31589614, 34953771, 34662459, 33639313, 34290017, 34806449, 35037466, 34671066, 33705824, 26139440, 33168999, 33437033, DurkieM2023[Article], 37345660, 37372410, ChenJM2023[Preprint], 37519231, 37231942, 35896062, 37418622, 20558538, 32939031, 35358475, 37543885)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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	2022-02-02	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 cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (46 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described as a likely hypomorphic allele, and has been reported in homozygous and compound heterozygous patients with polycystic kidney disease, but also in mildly affected heterozygous patients with renal cysts (ClinVar, PKD Mutation Database). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function through defective PC-1 cleavage, protein folding and trafficking (PMID: 23064367). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000192215	SCV001752531	pathogenic	Polycystic kidney disease, adult type	2021-06-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000192215	SCV002038531	pathogenic	Polycystic kidney disease, adult type	2021-06-09	criteria provided, single submitter	clinical testing	The PKD1 c.9829C>T (p.Arg3277Cys) variant is described as a hypomorphic allele proposed to modulate renal cyst development, which when detected in a homozygous or compound heterozygous state may result in a severe PKD phenotype but in a heterozygote state may cause a few cysts or no evidence of disease (Rossetti et al. 2009; Harris and Torres 2018). Across a selection of the available literature, the p.Arg3277Cys variant, a missense variant, has been identified in at least 17 individuals with polycystic kidney disease (PKD), including four in a homozygous state and six in a compound heterozygous state most of whom had severe, early-onset PKD (Rossetti et al. 2009; Vujic et al. 2010; Audrezet et al. 2016; Mantovani et al. 2020; Durkie et al. 2021). In a four generation consanguineous family in which the p.Arg3277Cys variant segregated with disease, the variant was also found in six individuals in a heterozygous state including five individuals presenting with a mild phenotype ranging from one to five simple cysts in adulthood and in one individual with no evidence of disease (Rossetti et al. 2009). Durkie et al. (2021) describe an additional individual heterozygous for the p.Arg3277Cys variant presenting with a severe, prenatal-onset phenotype and death shortly after birth, however a second, unidentified variant is suspected due to his unaffected father carrying the p.Arg3277Cys variant and his affected mother not having an identified variant. The p.Arg3277Cys variant was also found in at least five unaffected parents of an affected individual (Audrezet et al. 2016: Vujic et al. 2010; Durkie et al. 2021), although ages of the parents were not consistently specified. Control data are unavailable for this variant, which is reported at a frequency of 0.000453 in the European (non-Finnish) population of the Genome Aggregation Database v2.1.1. This allele frequency is high but may be consistent with reduced penetrance/hypomorphic allele. A knock-in mouse model found that heterozygous mice did not present with PKD but did find that homozygous, and compound heterozygous mice respectively demonstrated progressively more severe phenotypes consistent with human PKD patients, indicating the p.Arg3277Cys variant is dosage dependent and a hypomorphic modifier of the PKD phenotype (Hopp et al. 2012). Based on the collective evidence, the p.Arg3277Cys variant is classified as pathogenic (hypomorphic) for autosomal dominant polycystic kidney disease, generally associated with mild or no disease when detected in a heterozygous state and with a more severe, earlier-onset phenotype when detected in trans with a second variant.
Mendelics	RCV000192215	SCV002518861	pathogenic	Polycystic kidney disease, adult type	2022-05-04	criteria provided, single submitter	clinical testing
GeneReviews	RCV000192215	SCV000223894	not provided	Polycystic kidney disease, adult type		no assertion provided	literature only	Hypomorphic allele
Gharavi Laboratory, Columbia University	RCV000497386	SCV000920751	likely benign	not provided	2018-09-16	flagged submission	research
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254214	SCV001430283	uncertain significance	Autosomal dominant polycystic kidney disease	2019-01-01	flagged submission	research