ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.7636C>T (p.His2546Tyr) (rs200037070)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431943 SCV000520764 likely benign not specified 2016-07-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002121 SCV001159972 benign Polycystic kidney disease, adult type 2019-02-15 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001002121 SCV001369221 uncertain significance Polycystic kidney disease, adult type 2019-06-05 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: BP4.
Athena Diagnostics Inc RCV000431943 SCV001475265 benign not specified 2020-03-04 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292195 SCV001480919 likely benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.His2546Tyr variant was identified in 2 of 186 proband chromosomes (frequency: 0.010752688172043) from individuals or families with autosomal dominant polycystic kidney disease and was not identified in 200 control chromosomes from healthy individuals (Hoefele_2011_ 21115670). The variant was also identified in dbSNP (ID: rs200037070) as “With Likely benign allele”, in ClinVar (Likely Benign by GeneDx), LOVD 3.0 (3x as Likely Benign 1x as VUS), ADPKD Mutation Database (1x as Likely Neutral). The variant was not identified in PKD1-LOVD. The variant was also identified by our laboratory in 4 individuals with ADPKD however in one family the variant was identified in the proband and was not present in an adult family member with a clinical diagnosis of PKD suggesting that the variant does not have clinical significance. The variant was identified in control databases in 403 of 247588 chromosomes (2 homozygous) at a frequency of 0.002 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: African in 1 of 20394 chromosomes (freq: 0.00005), Other in 9 of 5890 chromosomes (freq: 0.002), Latino in 1 of 31996 chromosomes (freq: 0.00003), European Non-Finnish in 235 of 110126 chromosomes (freq: 0.002), Ashkenazi Jewish in 26 of 9530 chromosomes (freq: 0.003), Finnish in 131 of 22822 chromosomes (freq: 0.006); it was not observed in the East Asian, 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. The p.His2546 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.