Submissions for variant NM_138694.4(PKHD1):c.390+1G>T

gnomAD frequency: 0.00002  dbSNP: rs752327566

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780595	SCV000917995	likely pathogenic	Autosomal recessive polycystic kidney disease	2021-02-22	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.390+1G>T 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: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251768 control chromosomes (gnomAD and publication data). c.390+1G>T has been reported in the literature in an individual affected with Polycystic Kidney Disease (Furu_2003) as well as in one carrier for ARPKD (Thomas_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has 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.
Blueprint Genetics	RCV000788977	SCV000928285	likely pathogenic	not provided	2019-03-20	criteria provided, single submitter	clinical testing
Invitae	RCV000780595	SCV000931542	likely pathogenic	Autosomal recessive polycystic kidney disease	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 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 (rs752327566, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with clinical features of polycystic kidney disease (PMID: 12874454, 32203225, 33282801). This variant is also known as IVS5+1G>T. ClinVar contains an entry for this variant (Variation ID: 632942). 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.
GeneDx	RCV000788977	SCV001771621	likely pathogenic	not provided	2020-10-13	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Identified perinatally in a fetus with nephromegaly in whom no second PKD1 variant was identified (Furu et al., 2003); This variant is associated with the following publications: (PMID: 12874454, 25525159, 19940839)
Myriad Genetics, Inc.	RCV001810486	SCV002060107	likely pathogenic	Polycystic kidney disease 4	2021-10-25	criteria provided, single submitter	clinical testing	NM_138694.3(PKHD1):c.390+1G>T is a canonical splice site variant classified as likely pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. c.390+1G>T has been observed in cases with relevant disease (PMID: 12874454, 32203225, 33282801). Functional assessments of this variant are not available in the literature. c.390+1G>T has been observed in population frequency databases (gnomAD: NFE 0.004%). In summary, NM_138694.3(PKHD1):c.390+1G>T is a canonical splice site variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV001810486	SCV002784816	pathogenic	Polycystic kidney disease 4	2022-04-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001810486	SCV004202238	pathogenic	Polycystic kidney disease 4	2023-10-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000780595	SCV002083410	likely pathogenic	Autosomal recessive polycystic kidney disease	2017-03-16	no assertion criteria provided	clinical testing