ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.3424C>T (p.Arg1142Trp)

gnomAD frequency: 0.01272  dbSNP: rs142202785
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001001961 SCV001159759 benign Polycystic kidney disease, adult type 2018-09-04 criteria provided, single submitter clinical testing
GeneDx RCV001664615 SCV001874689 benign not provided 2020-04-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001001961 SCV002805547 likely benign Polycystic kidney disease, adult type 2021-09-27 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292386 SCV001480839 benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Arg1142Trp variant was not identified in the literature nor was it identified in ClinVar, Clinvitae, LOVD PKD1 databases. The variant was identified in dbSNP (ID: rs144557371) as “NA”, with a minor allele frequency of 0.01 (57 of 5000 chromosomes in1000 Genomes Project), the NHLBI GO Exome Sequencing Project in 5 of 8550 European American (frequency: 0.0006) and in 172 of 4340 African American alleles (frequency: 0.0.04),the Exome Aggregation Consortium database (August 8, 2016) in 386 (7 homozygous) of 53938 chromosomes (frequency: 0.007) in the following populations: African in 316 of 4896 chromosomes (frequency: 0.06), Latino in 23 of 3654 chromosomes (frequency: 0.006), European (Non-Finnish) in 42 of 28616 chromosomes (frequency: 0.001), Finnish in 1 of 1374 chromosomes (frequency: 0.0007), South Asian in 2 of 11042 chromosomes (frequency: 0.0002), East Asian in 1 of 3950 (frequency: 0.0003) and in Other in 1 of 406 chromosomes (frequency: 0.002), 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 variant was identified in the ADPKD Mutation Database (likely neutral), and PKD1-LOVD 3.0 (unknown effect). The variant was identified by our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.12178C>T, p.Gln4060X), increasing the likelihood that the variant does not have clinical significance. The p.Arg1142 residue is not 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 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, this variant meets our laboratory criteria to be classified as benign.

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