NM_001009944.3(PKD1):c.9829C>T (p.Arg3277Cys) AND Polycystic kidney disease, adult type

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: May 4, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000192215.26

Allele description

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

Gene:

PKD1:polycystin 1, transient receptor potential channel interacting [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

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

HGVS:

NC_000016.10:g.2099955G>A
NG_008617.1:g.43266C>T
NM_000296.4:c.9829C>T
NM_001009944.3:c.9829C>TMANE SELECT
NP_000287.4:p.Arg3277Cys
NP_001009944.2:p.Arg3277Cys
NP_001009944.3:p.Arg3277Cys
NC_000016.9:g.2149956G>A
NM_001009944.2:c.9829C>T
NM_001009944.2:c.9829C>T

Protein change:

R3277C

Links:

dbSNP: rs148812376

NCBI 1000 Genomes Browser:

rs148812376

Molecular consequence:

NM_000296.4:c.9829C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001009944.3:c.9829C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Polycystic kidney disease, adult type (PKD1)
Synonyms:: Polycystic Kidney, Autosomal Dominant; POLYCYSTIC KIDNEY DISEASE, ADULT, TYPE I; Polycystic kidney disease 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008263; MedGen: C3149841; OMIM: 173900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000223894	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001164388	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 3, 2018)	germline	research	PubMed (4) [See all records that cite these PMIDs] 19165178, 26139440, 23064367, 25741868
SCV001427194	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23064367, 25741868
SCV001752531	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 30, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002038531	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Jun 9, 2021)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19165178, 20301424, 20558538, 23064367, 26139440, 32457805, 33168999 Citation Link,
SCV002518861	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only, clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease.

Rossetti S, Kubly VJ, Consugar MB, Hopp K, Roy S, Horsley SW, Chauveau D, Rees L, Barratt TM, van't Hoff WG, Niaudet P, Torres VE, Harris PC.

Kidney Int. 2009 Apr;75(8):848-55. doi: 10.1038/ki.2008.686. Epub 2009 Jan 21. Erratum in: Kidney Int. 2009 Jun;75(12):1359. Kidney Int. 2010 Feb;77(4):368. Niaudet, W Patrick [corrected to Niaudet, Patrick]. Erratum in: Kidney Int. 2009 Jun 2;75(12):1359. doi: 10.1038/ki.2009.151.

PubMed [citation]

PMID:: 19165178
PMCID:: PMC2813773

See all PubMed Citations (8)

Details of each submission

From GeneReviews, SCV000223894.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Hypomorphic allele

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164388.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV001427194.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV001752531.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV002038531.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV002518861.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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