Submissions for variant NM_138694.4(PKHD1):c.2269A>C (p.Ile757Leu)

dbSNP: rs777183511

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000288236	SCV000345649	uncertain significance	not provided	2016-08-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000317551	SCV000464106	uncertain significance	Autosomal recessive polycystic kidney disease	2016-07-27	criteria provided, single submitter	clinical testing	The PKHD1 c.2269A>C (p.Ile757Leu) variant is a missense variant that has been reported in two studies, where it was found in a compound heterozygous state in two individuals with polycystic kidney disease (Rossetti et al. 2003; Sharp et al. 2005). This variant was absent from 300 control chromosomes. It is reported at a frequency of 0.00017 in the Latino population of the Exome Aggregation Consortium, but this frequency is based on two alleles only in a region of good sequencing coverage. Therefore, the variant is presumed to be rare. The evidence for this variant is limited. The p.Ile757Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
SIB Swiss Institute of Bioinformatics	RCV000317551	SCV000803597	uncertain significance	Autosomal recessive polycystic kidney disease	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.
Baylor Genetics	RCV000317551	SCV001163057	likely pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
GeneDx	RCV000288236	SCV001985430	uncertain significance	not provided	2022-04-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12846734, 15805161)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509355	SCV002819544	uncertain significance	not specified	2022-12-14	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.2269A>C (p.Ile757Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251132 control chromosomes (gnomAD). The variant, c.2269A>C, has been reported in the literature in at least three compound heterozygous individuals (including two fetal cases) who were affected with Polycystic Kidney with- or without hepatic involvement (Rossetti_2003, Sharp_2005, Burgmaier_2021).These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 VUS-possibly pathogenic.
Invitae	RCV000317551	SCV002931839	pathogenic	Autosomal recessive polycystic kidney disease	2023-08-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 not expected to disrupt PKHD1 protein function. ClinVar contains an entry for this variant (Variation ID: 290977). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 12846734, 15805161, 33940108; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs777183511, gnomAD 0.006%). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 757 of the PKHD1 protein (p.Ile757Leu).
Baylor Genetics	RCV003469249	SCV004204540	likely pathogenic	Polycystic kidney disease 4	2023-09-14	criteria provided, single submitter	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844826	SCV001876989	uncertain significance	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research