ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.7350+653A>G

gnomAD frequency: 0.00001  dbSNP: rs1240212722
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667179 SCV000791595 likely pathogenic Autosomal recessive polycystic kidney disease 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000667179 SCV001584109 pathogenic Autosomal recessive polycystic kidney disease 2023-11-13 criteria provided, single submitter clinical testing This sequence change falls in intron 46 of the PKHD1 gene. It does not directly change the encoded amino acid sequence of the PKHD1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 19021639). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS46+653A>G. ClinVar contains an entry for this variant (Variation ID: 551996). Studies have shown that this variant results in the inclusion of a pseudoexon and introduces a premature termination codon (PMID: 19021639). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002272320 SCV002557489 pathogenic Polycystic kidney disease 4 2022-09-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant intrafamilial variation of severity (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Sequencing of cDNA has demonstrated that this variant results in the formation of a pseudoexon. The insertion of the 116bp newly recognised pseudoexon is responsible for the creation of a premature stop codon in exon 47 and is predicted to cause nonsense-mediated decay (NMD) and loss of protein (PMID:19021639). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v3) for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic in ClinVar. It has also been reported in multiple individuals with autosomal recessive polycystic kidney disease (PMID:19021639) (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_138694.3(PKHD1):c.5895dupA; p.(Leu1966Thrfs*4)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV002272320 SCV002799583 pathogenic Polycystic kidney disease 4 2022-04-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000667179 SCV004020379 pathogenic Autosomal recessive polycystic kidney disease 2023-06-07 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.7350+653A>G is located at a position not widely known to affect splicing, however several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5' donor site. This has been confirmed via cDNA sequencing of patient tissues, which showed the variant transcript had inclusion of a pseudoexon that results in a predicted frameshift: p.Gly2451fs (Michel-Calemard_2009). The variant was absent in 31404 control chromosomes (gnomAD). c.7350+653A>G has been reported in the literature in the compound heterozygous state in multiple individuals affected with Polycystic Kidney And Hepatic Disease (Michel-Calemard_2009). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 19021639). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV002272320 SCV004204645 pathogenic Polycystic kidney disease 4 2023-05-31 criteria provided, single submitter clinical testing
OMIM RCV000667179 SCV000024503 pathogenic Autosomal recessive polycystic kidney disease 2009-02-01 no assertion criteria provided literature only

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