ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.6749C>T (p.Thr2250Met) (rs139971481)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517469 SCV000614521 benign not specified 2017-03-24 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658732 SCV000780519 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000989454 SCV000885918 uncertain significance Polycystic kidney disease, adult type 2019-02-21 criteria provided, single submitter clinical testing The PKD1 c.6749C>T, p.Thr2250Met variant (rs139971481) has been reported in individuals diagnosed with ADPKD (Irazabal 2011, Perrichot 2000, Reiterova 2013, Rossetti 2012) but has also been found to co-occur with truncating PKD1 variants (Mayo ADPKD database). In one individual, the p.Thr2250Met variant was found in-trans with a truncating PKD1 variant and correlated with a more severe polycystic disorder, suggesting a possible modifier effect (Reiterova 2013). Individuals heterozygous for this variant exhibit either a mild cystic disease or no clinical phenotypes (Kleffman 2012, Reiterova 2013). This variant is found in the non-Finnish European population with an overall allele frequency of 0.35% (444/127104 alleles, including three homozygotes) in the Genome Aggregation Database. The threonine at codon 2250 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Although the population frequency and clinical phenotypes suggest that the p.Thr2250Met may not be a causative variant on its own, its potential effect as a disease modifier cannot be excluded. Thus, the clinical significance of p.Thr2250Met cannot be determined with certainty. References: Mayo ADPKD database: Irazabal M et al. Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011 Jun;6(6):1274-85. Kleffman J et al. Dosage-sensitive network in polycystic kidney and liver disease: multiple mutations cause severe hepatic and neurological complications. J Hepatol. 2012 Aug;57(2):476-7. Perrichot R et al. Novel mutations in the duplicated region of PKD1 gene. Eur J Hum Genet. 2000 May;8(5):353-9. Reiterova J et al. Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele. BMC Nephrol. 2013 Mar 15;14:59.
Mendelics RCV000989454 SCV001139784 likely benign Polycystic kidney disease, adult type 2019-05-28 criteria provided, single submitter clinical testing

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