ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.971G>T (p.Arg324Leu) (rs199476099)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000008688 SCV000884320 benign Polycystic kidney disease, adult type 2019-04-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000756490 SCV001150735 likely pathogenic not provided 2016-06-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000008688 SCV001370129 uncertain significance Polycystic kidney disease, adult type 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS1,PP3,PP4,BP6,BS2.
GeneDx RCV000756490 SCV001791088 likely benign not provided 2020-09-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10364515, 12662927, 27499327, 19759016, 21115670, 17582161)
OMIM RCV000008688 SCV000028897 pathogenic Polycystic kidney disease, adult type 1999-07-01 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000008688 SCV001142453 uncertain significance Polycystic kidney disease, adult type 2020-01-06 no assertion criteria provided curation NM_001009944.2:c.971G>T in the PKD1 gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. This variant has been detected in a individual with autosomal dominant polycystic kidney disease (PMID: 10364515). Benign computational verdict because benign predictions from DEOGEN2, EIGEN, FATHMM-MKL, PrimateAI and SIFT. As a dominant inheritance manner, a total of 626 allleles was detected in gnomAD database which is a evidence to against its pathogenicity, although the adult-onset should be considered. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP4, BP4.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292035 SCV001480652 benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Arg324Leu variant was identified in 6 of 720 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Thomas 1999, Hoefele 2011, Rossetti 2007). The variant was also identified in dbSNP (ID: rs199476099) as “With Pathogenic allele”, Clinvitae (classified as pathogenic by ClinVar), ClinVar (classified as pathogenic by OMIM), MutDB, ADPKD Mutation Database (classified as likely neutral), and PKD1-LOVD 3.0 (probably does not affect function). This variant was identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), the NHLBI GO Exome Sequencing Project in 17 of 7568 European American and in 1 of 3614 African American alleles, the genome Aggregation Database (beta, October 19th 2016) in 501 (1 homozygous) of 192856 chromosomes (freq. 0.003), the Exome Aggregation Consortium database (August 8th 2016) in 157 (1 homozygous) of 24970 chromosomes (freq. 0.006) in the following populations: European in 139 of 11896 chromosomes (freq. 0.01), Finnish in 9 of 402 chromosomes (freq. 0.02), Latino in 6 of 1292 chromosomes (freq. 0.004), African in 2 of 1452 chromosomes (freq. 0.001), Other in 1 of 204 chromosomes (freq. 0.005), increasing the likelihood this could be a low frequency benign variant. The p.Arg324 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 addition, the variant was identified with an unspecified co-occurring pathogenic variant increasing the likelihood that the p.Arg324Leu variant does not have clinical significance (Rossetti 2007). It was also identified in one individual from our lab in homozygous form, and with a co-occurring PKD2 pathogenic variant (c.1662G>A, p.Trp554X) increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign.

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