ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.12826C>T (p.Arg4276Trp) (rs114251396)

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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 RCV000989444 SCV000885956 likely benign Polycystic kidney disease, adult type 2019-04-06 criteria provided, single submitter clinical testing
Mendelics RCV000989444 SCV001139770 uncertain significance Polycystic kidney disease, adult type 2019-05-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV001288333 SCV001475353 benign not specified 2020-08-03 criteria provided, single submitter clinical testing
GeneDx RCV001706706 SCV001873339 benign not provided 2020-10-02 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32398770, 30816285, 17582161, 22383692, 22008521, 10200984, 20981092, 23431072, 22995991, 22508176)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292264 SCV001480923 likely benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Arg4276Trp variant was identified in 12 of 3064 proband chromosomes (frequency: 0.004) from French, Italian, Spanish, and North American individuals or families with ADPKD (with or without family history), and was not identified in 459 control chromosomes from healthy individuals (Audrézet 2012, Carrera 2016, Rossetti 2012, Bataille 2011, Badenas 1999). The variant was found to co-occur with several PKD1 pathogenic/indeterminate variants (PKD1: p.Leu56Argfs*15, IVS37-10C3A/S3673fsX3674, Asp3781_Val3782insGlu, PKD2: R878del) and or multiple variants (PKD1 A4091A-G, V4058, V4044, and L4136L-T, Rossetti 2007, Carrera 2016, Bataille 2011, Badenas 1999). Ball et al (2012) used a public software tool for genome interpretation and a public database of variant interpretations, to review 10 presumed healthy genomes, the variant was identified in one participant and classified as uncertain significance. The variant was also identified in dbSNP (ID: rs114251396) as “NA”, the ADPKD Mutation Database (classification indeterminate), and PKD1-LOVD 3.0 (classification possibly damaging), the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002), the NHLBI GO Exome Sequencing Project in 28 of 8154 European American alleles (frequency: 0.003), and in the Exome Aggregation Consortium database (August 8, 2016) in 378 (2 homozygous) of 58652 chromosomes (frequency: 0.0064) in the following populations: Finnish in 65 of 1942 chromosomes (frequency: 0.03), European (Non-Finnish) in 282 of 32154 chromosomes (frequency: 0.009), Other in 2 of 392 chromosomes (frequency: 0.005), Latino in 9 of 3938 chromosomes (frequency: 0.002), South Asian in 16 of 11214 chromosomes (frequency: 0.001), and African in 4 of 4308 chromosomes (frequency: 0.0009); but was not seen in the East Asian population. The p.Arg4276 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of five 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 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.

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