ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.7927C>T (p.Arg2643Cys)

dbSNP: rs1452322332
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001091876 SCV001248136 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001252966 SCV001427176 pathogenic Polycystic kidney disease, adult type 2022-06-24 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 (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (19 heterozygotes, 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) 0600 - Variant is located in the annotated GPCR-autoproteolysis inducing domain (PMID: 22333914). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative variant (p.(Arg2643Pro)) has also been shown to cause autosomal dominant polycystic kidney disease (PMID: 27499327). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in individuals with autosomal dominant polycystic kidney disease, and classified as likely pathogenic and pathogenic (ClinVar, VCGS, PMID: 17574468, 22508176, 27165007, pkdb.mayo.edu). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that transfected HEK293 cells have disrupted cleavage (PMID: 17574468). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research RCV001254251 SCV001430291 likely pathogenic Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
GeneDx RCV001091876 SCV002571668 likely pathogenic not provided 2023-06-16 criteria provided, single submitter clinical testing Published functional studies demonstrate this variant disrupts PKD1 cleavage (Garcia-Gonzalez et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27165007, 17574468, 22508176, 32939031, 33437033)
Fulgent Genetics, Fulgent Genetics RCV001252966 SCV002809810 likely pathogenic Polycystic kidney disease, adult type 2022-03-10 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292442 SCV001480938 likely pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Arg2643Cys variant was identified in 2 of 1564 proband chromosomes (frequency: 0.001) from individuals or families with ADPKD and was not identified in 342 control chromosomes from healthy individuals (Audrézet 2012, Garcia-Gonzalez 2007). The variant was also identified in the ADPKD Mutation database 6X as highly likely pathogenic. The variant was not identified in dbSNP, ClinVar, ClinVar, LOVD 3.0, or PKD1-LOVD. The variant was identified in control databases in 1 of 227680 chromosomes at a frequency of 0.000004 in the following population: European Non-Finnish in 1 of 106166 chromosomes (freq. 0.000009), but was not seen in African, Latino, Ashkenazi Jewish, East Asian, European Finnish and other populations (Genome Aggregation Consortium Feb 27, 2017). One study used several major criteria to judge the pathogenicity of the p.Arg2643Cys missense variant. The p.Arg2643Cys variant was confirmed to disrupt cleavage by expressing this variant in HEK293 cells and was classified as likely pathogenic (Garcia-Gonzalez 2007). The p.Arg2643Cys residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as likely pathogenic.

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