Submissions for variant NM_138694.4(PKHD1):c.8317G>T (p.Val2773Leu)

gnomAD frequency: 0.00001  dbSNP: rs747322128

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000633431	SCV000754655	pathogenic	Autosomal recessive polycystic kidney disease	2023-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2773 of the PKHD1 protein (p.Val2773Leu). This variant is present in population databases (rs747322128, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive polycystic kidney disease (PMID: 16133180, 19940839; 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: 528299). 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) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000633431	SCV000797808	likely pathogenic	Autosomal recessive polycystic kidney disease	2018-02-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002499047	SCV002809349	likely pathogenic	Polycystic kidney disease 4	2022-05-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000633431	SCV002819861	pathogenic	Autosomal recessive polycystic kidney disease	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.8317G>T (p.Val2773Leu) results in a conservative amino acid change located in the G8 domain (IPR019316) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251162 control chromosomes (gnomAD). c.8317G>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Losekoot_2005, Denamur_2010, Balci_2017, Groopman_2019, Burgmaier_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV002499047	SCV004037354	likely pathogenic	Polycystic kidney disease 4	2020-02-24	criteria provided, single submitter	clinical testing	The c.8317G>T variant is a heterozygous, single base pair substitution at nucleotide 8317 in exon 53 of 67 of the PKHD1 gene, resulting in the substitution of a well-conserved, Valine residue at amino acid position 2773 to a non-polar Leucine residue. The c.8317G>T variant is observed in gnomAD in heterozygous but not homozygous form indicating it is not a common benign variant in the populations represented in this database. The variant has been observed in trans with a pathogenic variant in an individual with AR Polycystic Kidney Disease (PMID: 16133180, 28170084).
PreventionGenetics, part of Exact Sciences	RCV003392471	SCV004119782	likely pathogenic	PKHD1-related disorder	2022-09-21	criteria provided, single submitter	clinical testing	The PKHD1 c.8317G>T variant is predicted to result in the amino acid substitution p.Val2773Leu. This variant has been reported together with different pathogenic variants in individuals with polycystic kidney disease (Losekoot et al. 2005. PubMed ID: 16133180; Balci et al. 2017. PubMed ID: 28170084). At PreventionGenetics, this variant was also found with different pathogenic variants in individuals tested for polycystic kidney disease. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51656157-C-A). In summary, this variant is interpreted as likely pathogenic.
Baylor Genetics	RCV002499047	SCV004204810	likely pathogenic	Polycystic kidney disease 4	2022-01-31	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000681915	SCV000809398	likely pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Natera, Inc.	RCV000633431	SCV001455066	uncertain significance	Autosomal recessive polycystic kidney disease	2020-09-16	no assertion criteria provided	clinical testing
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV002499047	SCV004024146	likely pathogenic	Polycystic kidney disease 4		no assertion criteria provided	research