ClinVar Miner

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

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Total submissions: 6
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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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292268 SCV001480927 likely benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Thr2250Met variant was identified in 9 of 932 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Irazabal 2011, Paul 2014, Perrichot 2000, Rossetti 2012). The variant was also identified in dbSNP (ID: rs139971481) as “N/A”, the ADPKD Mutation Database (classified as likely neutral) and PKD1-LOVD 3.0 (classified as unknown effect). This variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.001), the NHLBI GO Exome Sequencing Project in 24 of 8584 European American and in 3 of 4388 African American alleles, the Exome Aggregation Consortium database (August 8th 2016) in 262 (4 homozygous) of 119152 chromosomes (freq. 0.002) in the following populations: European in 204 of 64980 chromosomes (freq. 0.003), Latino in 26 of 11528 chromosomes (freq. 0.002), Asian in 26 of 16500 chromosomes (freq. 0.002), African in 3 of 10108 chromosomes (freq. 0.0003), Finnish in 2 of 6588 chromosomes (freq. 0.0003) and Other in 1 of 880 chromosomes (freq. 0.001), increasing the likelihood this could be a low frequency benign variant. 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.Thr2250 residue is 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In two different case studies suggest the variant has a dosage effect and is most likely an incompletely penetrant allele (Kleffmann 2012, Reiterova 2013). However in the Kleffman study they report a 39 year old female homozygous for the p.The2250Met variant who does not have kidney cysts, suggesting that this variant may not cause typical polycystic kidney disease. This variant located in the REJ domain of PC-1 and cleavage of PC-1 at the GPS site can be affected by variants in this domain, however, analysis by Paul (2014) did not show that p.Thr2250Met variant influences this cleavage. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000658732 SCV001926690 likely benign not provided no assertion criteria provided clinical testing

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