Submissions for variant NM_138694.4(PKHD1):c.6900C>T (p.Asn2300=)

gnomAD frequency: 0.00004  dbSNP: rs776060304

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674293	SCV000799604	uncertain significance	Autosomal recessive polycystic kidney disease	2018-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000674293	SCV001576172	pathogenic	Autosomal recessive polycystic kidney disease	2023-09-19	criteria provided, single submitter	clinical testing	This sequence change affects codon 2300 of the PKHD1 mRNA. It is a 'silent' change, meaning that it does not 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 present in population databases (rs776060304, gnomAD 0.004%). This variant has been observed in individual(s) with polycystic kidney disease (PMID: 15698423, 15805161, 28170084; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558073). Studies have shown that this variant results in aberrant mRNA splicing and introduces a premature termination codon (PMID: 28170084). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001565179	SCV001788476	pathogenic	not provided	2024-07-03	criteria provided, single submitter	clinical testing	Published functional studies suggest an aberrant splice effect, resulting in a shorter, out-of-frame transcript (PMID: 28170084, 33059616); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15698423, 15805161, 33059616, 28170084, 33940108)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000674293	SCV002511956	likely pathogenic	Autosomal recessive polycystic kidney disease	2022-04-27	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.6900C>T alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Two predict the variant strengthens a cryptic 3' acceptor site. One study reported the variant resulted in the skipping of 47 nucleotides of exon 43 resulting in a reading frame shift (Balci_2017), while a second study reported that while this alternate splicing of exon 43 occurs at a basal level in control cells, it is promoted by the synonymous change shifting the expression ratio in favour of a shorter, out-of-frame transcript (Molinari_2020). The variant allele was found at a frequency of 1.6e-05 in 251312 control chromosomes. c.6900C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease in the compound heterozygous and homozygous state (Balci_2017, Molinari_2020, Burgmaier_2021). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One submitter classified the variant as likely pathogenic while two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003472168	SCV004202237	likely pathogenic	Polycystic kidney disease 4	2024-02-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411585	SCV004116119	pathogenic	PKHD1-related disorder	2024-07-07	no assertion criteria provided	clinical testing	The PKHD1 c.6900C>T is a noncoding alteration. This variant has been reported in the homozygous and compound heterozygous state in individuals with PKHD1-related disease (Balci et al. 2017. PubMed ID: 28170084; Table S3, Burgmaier et al. 2021. PubMed ID: 33940108). The c.6900C site has been reported to be an exonic splicing enhancer and the C to T change caused aberrant mRNA splicing (a 47-nucleotide loss), resulting in a frameshift and premature protein termination (Balci et al. 2017. PubMed ID: 28170084; Molinari et al. 2020. PubMed ID: 33059616). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.