ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.7429C>T (p.Arg2477Cys) (rs376283361)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000248177 SCV000305775 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000766664 SCV000617183 uncertain significance not provided 2015-10-08 criteria provided, single submitter clinical testing The R2477C variant in the PKD1 gene has been reported previously in an individual with polycystic kidney disease. However, this individual reportedly carried a second missense variant in the PKD1 gene that segregated with the disease, while the R2477C variant reportedly did not segregate with the disease (Rossetti et al., 2007). The R2477C variant was not observed at any significant frequency in approximately 4,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2477C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (R2477H) has been reported in association with polycystic kidney disease type 1 (Chang et al., 2013), supporting the functional importance of this residue. We interpret R2477C as a variant of uncertain significance.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626652 SCV000747354 uncertain significance Clubfoot; Polycystic kidney disease; Narrow chest; Hyperechogenic kidneys 2017-01-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000766664 SCV001553932 uncertain significance not provided no assertion criteria provided clinical testing The PKD1 p.R2477C variant was identified in a family with polycystickidney disease along with an F3168L variant, however only the F3168L variant segregated with disease (Rossetti_2007_PMID:17582161). The variant was also identified in dbSNP (ID: rs376283361), ClinVar (classified as a VUS by GeneDx and Centre for Mendelian Genomics, University Medical Centre Ljubljana and as likely benign by Prevention Genetics), LOVD 3.0 (classified as likely benign) and the ADPKD Mutation Database (classified as likely neutral). The variant was identified in control databases in 248 of 218070 chromosomes at a frequency of 0.001137 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 83 of 26454 chromosomes (freq: 0.003138), European (Finnish) in 31 of 13408 chromosomes (freq: 0.002312), Ashkenazi Jewish in 21 of 9226 chromosomes (freq: 0.002276), European (non-Finnish) in 97 of 97806 chromosomes (freq: 0.000992), Other in 5 of 6038 chromosomes (freq: 0.000828), Latino in 10 of 30478 chromosomes (freq: 0.000328) and East Asian in 1 of 16028 chromosomes (freq: 0.000062), but was not observed in the African population. The p.Arg2477 residue is conserved in mammals and three of four computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; 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) 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. This variant is classified as a variant of uncertain significance.

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