ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.977-2A>G

dbSNP: rs2533444880
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002471641 SCV002769057 likely pathogenic Polycystic kidney disease 4 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. The 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. Significant intrafamilial variation in disease severity has been reported (GeneReviews). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. Skipping of adjacent exon 14 is predicted to result in a frameshift. (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 0703 - Another canonical splice site variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. A different variant in the same splice site (c.977-1G>A) has been shown to cause polycystic kidney disease (ClinVar, PMID: 12506140). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics RCV002471641 SCV004204579 likely pathogenic Polycystic kidney disease 4 2023-08-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002471641 SCV005671040 likely pathogenic Polycystic kidney disease 4 2024-02-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005098452 SCV005798885 pathogenic Autosomal recessive polycystic kidney disease 2024-02-14 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 of the PKHD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 12506140). ClinVar contains an entry for this variant (Variation ID: 1805223). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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