ClinVar Miner

Submissions for variant NM_000297.4(PKD2):c.1319+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1131692280
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000496001 SCV000584107 pathogenic Polycystic kidney disease 2 2015-08-07 criteria provided, single submitter research
Invitae RCV000542204 SCV000658964 pathogenic Autosomal dominant polycystic kidney disease 2019-11-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). Disruption of this splice site has been reported in families affected with polycystic kidney disease (PMID: 11007674, 12707387, 22383692). It is also known as IVS5+1G>A in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 5 of the PKD2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics RCV000622691 SCV000741183 pathogenic Inborn genetic diseases 2023-09-11 criteria provided, single submitter clinical testing The c.1319+1G>A intronic variant results from a G to A substitution one nucleotide(s) after coding exon 5 of the PKD2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/282036) total alleles studied. The highest observed frequency was 0.012% (3/24960) of African alleles. This mutation has been reported in multiple individuals with a clinical diagnosis of polycystic kidney disease (Torra, 2000; Rossetti, 2012). In one individual with polycystic kidney disease, this mutation was identified in conjunction with a missense variant in PKD1 (Magistroni, 2003). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Athena Diagnostics Inc RCV000992621 SCV001145029 pathogenic not provided 2020-12-30 criteria provided, single submitter clinical testing This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000496001 SCV001158343 pathogenic Polycystic kidney disease 2 2019-03-27 criteria provided, single submitter clinical testing The PKD2 c.1319+1G>A variant (rs1131692280), also known as IVS5+1G>A, is reported in the literature in multiple individuals and families affected with autosomal dominant polycystic kidney disease (ADPKD) (Magistroni 2003, Rossetti 2012, Tan 2009, Torra 2000). This variant is found on only three chromosomes (3/282036 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 430967). This variant abolishes the canonical splice donor site of intron 5, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: Magistroni R et al. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2003 May;14(5):1164-74. Rossetti S et al. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012 May;23(5):915-33. Tan YC et al. Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease. Hum Mutat. 2009 Feb;30(2):264-73. Torra R et al. Increased prevalence of polycystic kidney disease type 2 among elderly polycystic patients. Am J Kidney Dis. 2000 Oct;36(4):728-34.
GeneDx RCV000992621 SCV002099583 likely pathogenic not provided 2022-10-11 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 11007674, 29790872, 12707387, 18837007, 22383692, 27499327, 35314260)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000496001 SCV002568301 likely pathogenic Polycystic kidney disease 2 2022-04-21 criteria provided, single submitter clinical testing PVS1 PM2
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292205 SCV001480957 pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD2 c.1319+1G>A variant was identified in 9 of 1178 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Hwang 2016, Magistroni 2003, Rossetti 2012, Tan 2008, Torra 2000). The variant was also identified in dbSNP (ID: rs1131692280) with “Pathogenic allele”, in ClinVar (classified pathogenic by Invitae, Ambry Genetics and Hudson Alpha Institute for Biotechnology), LOVD 3.0 (2x), and the ADPKD Mutation Database (classified as definitely pathogenic). The variant was not identified in the PKD1-LOVD database. The variant was identified in 3 of 276406 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 3 of 24026 chromosomes (freq: 0.0001); it was not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.1319+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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