ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.4264G>A (p.Ala1422Thr)

gnomAD frequency: 0.00485  dbSNP: rs140980374
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Preventiongenetics, part of Exact Sciences RCV000254327 SCV000305739 likely benign not specified criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755353 SCV000604788 benign Polycystic kidney disease, adult type 2019-12-20 criteria provided, single submitter clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research RCV001254282 SCV001430248 likely benign Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
GeneDx RCV001565318 SCV001788644 likely benign not provided 2020-10-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17582161, 22383692)
CeGaT Center for Human Genetics Tuebingen RCV001565318 SCV004142886 benign not provided 2022-06-01 criteria provided, single submitter clinical testing PKD1: BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001291898 SCV000592772 benign Polycystic kidney disease no assertion criteria provided clinical testing PKD1, EXON15, c.4264G>A, p.Ala1422Thr, (Alias c.4475G>A), Heterozygous, Benign The PKD1 p.Ala1422Thr variant was identified in 3 of 864 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD, and was not identified in 242 control chromosomes from healthy individuals (Rossetti 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs140980374) “With clinical significance allele not available”, in 1000 Genomes Project in 22 of 5000 chromosomes (frequency: 0.004), in NHLBI GO Exome Sequencing Project (ESP) in 72 of 8592 European American (frequency: 0.008) and 9 in 4394 (frequency: 0.002) African American alleles. This variant was identified in the Exome Aggregation Consortium database (March 2016) in 713 (5 homozygous) of 118566 chromosomes (freq. 0.006) in the following populations: other in 10 of 880 chromosomes (freq. 0.01), European (Non-Finnish) in 565 of 64594 chromosomes (freq. 0.009), South Asian in 76 of 16504 chromosomes (freq. 0.005), Latino in 45 of 11538 chromosomes (freq. 0.004), Finnish in 7 of 6602 chromosomes (freq. 0.001), and African in 10 of 9854 chromosomes (freq. 0.001), but was not seen in the East Asian populations, increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. Furthermore, the variant is listed in the GeneInsight COGR database as benign, as likely neutral in the ADPKD Mutation Database, and listed with no classification in the PKD1-LOVD 3.0 database. The p.Ala1422 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Furthermore, the variant amino acid “Threonine” is present in macaque, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. 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. The variant was observed as co-occurring with another pathogenic variant in one individual identified by our laboratory, increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000254327 SCV001954182 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001565318 SCV001975246 likely benign not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001565318 SCV002037007 likely benign not provided no assertion criteria provided clinical testing

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