ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.11398+2T>C

gnomAD frequency: 0.00001  dbSNP: rs754038777
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000812342 SCV000952653 likely pathogenic Autosomal recessive polycystic kidney disease 2022-01-11 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 656036). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. This variant is present in population databases (rs754038777, gnomAD 0.002%). This sequence change affects a donor splice site in intron 63 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).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470987 SCV002768010 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) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tool and affected nucleotide is highly conserved. (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This splice variant (c.11398+1G>A) has been reported in a compound heterozygous patient with autosomal recessive polycystic kidney disease (PMID: 26673778). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an individual. This variant has been reported as likely pathogenic (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_138694.3:c.5895dup; p.(Leu1966Thrfs*4)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc. RCV000812342 SCV002075483 likely pathogenic Autosomal recessive polycystic kidney disease 2017-11-07 no assertion criteria provided clinical testing

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