ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik 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 2019-02-04 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_001009944.2(PKD1):c.7927C>T, has been identified in exon 21 of 46 of the PKD1 gene. The variant is predicted to result in a major amino acid change from arginine to cysteine at position 2643 of the protein (NP_001009944.2(PKD1):p.(Arg2643Cys)). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within the GPCR-autoproteolysis inducing (Arac, D. et al., 2012) 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 0.0004% (1 heterozygote). An alternative residue change has been reported in the gnomAD database at a frequency of 0.008%. The variant has been previously described as pathogenic in patients with autosomal dominant polycystic kidney disease (ADPKD) (Garcia-Gonzalez, M.A. et al., 2007; Mallawaarachchi, A.C. et al., 2016). Additionally, studies showed that this variant impacts protein function (Garcia-Gonzalez, M.A. et al., 2007). Despite analysis of maternal sample, the inheritance of this variant remains unsolved. 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 RCV001254251 SCV001430291 likely pathogenic Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
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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