ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.8087T>C (p.Leu2696Pro)

dbSNP: rs201238819
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002477 SCV001160425 uncertain significance Polycystic kidney disease, adult type 2019-03-22 criteria provided, single submitter clinical testing The PKD1 c.8087T>C; p.Leu2696Pro variant (rs201238819) is reported in the literature in an individual affected with autosomal dominant polycystic kidney disease, but it was not considered to be disease-causing (Rossetti 2007). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (33/84186 alleles) in the Genome Aggregation Database. The leucine at codon 2696 is not conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Leu2696Pro variant is uncertain at this time. References: Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292023 SCV001480621 uncertain significance Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Leu2696Pro variant was identified in 1 of 404 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD however this variant was not considered disease causing because of the highly nonconservative nature of this site in orthologs (Rossetti 2007). This variant was also identified in the ADPKD Mutation Database (classified as likely neutral by Athena Diagnostics). The variant was not identified in LOVD 3.0 or PKD1-LOVD databases. The variant was identified in control databases in 25 of 164086 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 25 of 66866 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. An alternative substitution at this position resulting in a different amino acid change (c.8087T>G, p.Leu2696Arg) was identified by our laboratory and classified as benign (this is the substitution recorded for this position in dbSNP (rs201238819) and ClinVar). The p.Leu2696 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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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