ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.10531C>G (p.Leu3511Val) (rs141946034)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000252033 SCV000305667 likely benign not specified criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000252033 SCV001475255 benign not specified 2020-07-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001291845 SCV000592846 likely benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Leu3511Val variant was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD in a validation study analyzing PKD1 and PKD2 genes using next-generation sequencing (Rossetti 2012). The variant was also identified in dbSNP (ID: rs141946034) as “NA”, ClinVar (classified as likely benign by Prevention Genetics), the ADPKD Mutation Database (classified likely neutral), and PKD1-LOVD 3.0 (unclassified). This variant was also identified in the NHLBI GO Exome Sequencing Project in 9 of 8588 European American alleles (frequency: 0.001), in 1 of 4386 African American alleles (frequency: 0.0002), and the Exome Aggregation Consortium database (August 8, 2016) in 201 (1 homozygous) of 81294 chromosomes (freq. 0.002) in the following populations: Finnish in 16 of 3556 chromosomes (freq. 0.005), European (Non-Finnish) in 184 of 44310 chromosomes (freq. 0.004), and Latino in 1 of 7714 chromosomes (freq. 0.0001), but was not seen in African, East Asian, Other, and South Asian populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in this case with a co-occurring pathogenic PKD1 variant (c.4461delC), increasing the likelihood that the p.Leu3511Val variant does not have clinical significance. The p.Leu3511 residue is conserved in mammals and lower organisms, except the variant amino acid Val is present in chicken, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. HumanSpliceFinder and MaxEntScan predict an altered 5' splice site in this region and we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site; this is not very predictive of pathogenicity. 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 benign role for this variant. This variant is classified as likely benign.

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