ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.9499A>T (p.Ile3167Phe) (rs139945204)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000710171 SCV000604808 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710171 SCV000614561 likely benign not provided 2017-05-25 criteria provided, single submitter clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory,Garvan Institute of Medical Research RCV001254209 SCV001430278 likely benign Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000735684 SCV000863828 uncertain significance Polycystic kidney disease, adult type 2018-03-07 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292326 SCV001481107 uncertain significance Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Ile3167Phe variant was identified in 1 of 90 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Rossetti_2002_11967008). The variant was also identified in dbSNP (ID: rs139945204) as “NA”, ClinVar (classified as uncertain significance by ARUP), LOVD 3.0 (1X) and ADPKD Mutation Database (as indeterminate), and was not identified in GeneInsight-COGR and PKD1-LOVD. The variant was identified in control databases in 333 (1 homozygous) of 276076 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 7 of 6438 chromosomes (freq: 0.001), Latino in 2 of 34416 chromosomes (freq: 0.00006), European Non-Finnish in 262 (1 homozygous) of 125774 chromosomes (freq: 0.002), European Finnish in 42 of 25790 chromosomes (freq: 0.002), and South Asian in 20 of 30774 chromosomes (freq: 0.0007) while not observed in the African, Ashkenazi Jewish and East Asian population. 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.Ile3167 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Phe 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, 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. This variant is classified as a variant of uncertain significance.

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