Submissions for variant NM_138694.4(PKHD1):c.2216C>T (p.Pro739Leu)

gnomAD frequency: 0.00004  dbSNP: rs758352210

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664559	SCV000788543	uncertain significance	Autosomal recessive polycystic kidney disease	2017-12-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000664559	SCV001163058	likely pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV000664559	SCV001425224	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
Invitae	RCV000664559	SCV002133480	pathogenic	Autosomal recessive polycystic kidney disease	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 739 of the PKHD1 protein (p.Pro739Leu). This variant is present in population databases (rs758352210, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease and/or clinical features of PKHD1-related conditions (PMID: 12846734, 24162162, 32939031, 33532864). 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: 549965). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000664559	SCV002547684	likely pathogenic	Autosomal recessive polycystic kidney disease	2022-05-31	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.2216C>T (p.Pro739Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251216 control chromosomes. c.2216C>T has been reported in the literature as compound heterozygous genotypes in multiple well characterized and comprehensively genotyped individuals affected with Autosomal recessive polycystic kidney disease (example, Rossetti_2003, Krall_2014, Jayasinghe_2021, Domingo-Gallego_2022, Burgmaier_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003472063	SCV004202234	likely pathogenic	Polycystic kidney disease 4	2023-10-20	criteria provided, single submitter	clinical testing