ClinVar Miner

Submissions for variant NM_138694.4(PKHD1):c.53-1G>A

gnomAD frequency: 0.00001  dbSNP: rs775511838
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666433 SCV000790725 likely pathogenic Autosomal recessive polycystic kidney disease 2017-04-26 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000666433 SCV001398403 likely pathogenic Autosomal recessive polycystic kidney disease 2023-11-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 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 present in population databases (rs775511838, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with clinical features of PKHD1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 551384). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000666433 SCV001432059 likely pathogenic Autosomal recessive polycystic kidney disease 2020-08-28 criteria provided, single submitter clinical testing Variant summary: PKHD1 c.53-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251300 control chromosomes (gnomAD). To our knowledge, no occurrence of c.53-1G>A in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002499152 SCV002807312 likely pathogenic Polycystic kidney disease 4 2021-11-09 criteria provided, single submitter clinical testing
Baylor Genetics RCV002499152 SCV004204551 likely pathogenic Polycystic kidney disease 4 2023-09-08 criteria provided, single submitter clinical testing
Natera, Inc. RCV000666433 SCV002083430 likely pathogenic Autosomal recessive polycystic kidney disease 2019-01-10 no assertion criteria provided clinical testing

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