Submissions for variant NM_138694.4(PKHD1):c.51A>G (p.Ala17=)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003037172	SCV003439468	pathogenic	Autosomal recessive polycystic kidney disease	2022-10-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 28364132; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 17 of the PKHD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKHD1 protein. It affects a nucleotide within the consensus splice site.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003037172	SCV004037783	likely pathogenic	Autosomal recessive polycystic kidney disease	2023-08-30	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.51A>G (p.Ala17Ala) alters a non-conserved nucleotide located close to a canonical splice site, specifically the penultimate nucleotide of Exon 2, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, finding that the variant resulted in utilization of an alternative downstream splice donor sit and lead to a frameshift (p.Val18GlyfsX3; e.g., Ebner_2017). The variant was absent in 251328 control chromosomes (gnomAD). c.51A>G has been reported in the literature in at least two compound heterozygous siblings affected with Polycystic Kidney And Hepatic Disease (e.g., Bergmann_2005, Ebner_2017, Ajiri_2011), and the variant was found to segregate with disease in related individuals. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant displayed high penetrance and behaved as a loss-of-function mutation in vitro (e.g., Ebner_2017). The following publications have been ascertained in the context of this evaluation (PMID: 35812281, 15698423, 28364132). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.