Submissions for variant NM_138694.4(PKHD1):c.2864T>G (p.Phe955Cys)

gnomAD frequency: 0.00001  dbSNP: rs777158800

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788922	SCV000928215	uncertain significance	not provided	2019-02-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035971	SCV001199311	pathogenic	Autosomal recessive polycystic kidney disease	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 955 of the PKHD1 protein (p.Phe955Cys). This variant is present in population databases (rs777158800, gnomAD 0.003%). This missense change has been observed in individual(s) with polycystic kidney disease (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: 636948). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000788922	SCV002588401	uncertain significance	not provided	2022-04-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV001035971	SCV001463314	uncertain significance	Autosomal recessive polycystic kidney disease	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292497	SCV001480613	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Phe955Cys variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, or RWTH AAachen University ARPKD databases. The variant was identified in dbSNP (ID: rs777158800). The variant was also identified in control databases in 3 of 245556 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 3 of 111208 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Phe955 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the phenylalanine variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The identification of this variant in an individual with a co-occurring pathogenic variant and in the context of a clinical presentation consistent with ARPKD increases the likelihood this variant may have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003928273	SCV004742229	pathogenic	PKHD1-related disorder	2024-02-16	no assertion criteria provided	clinical testing	The PKHD1 c.2864T>G variant is predicted to result in the amino acid substitution p.Phe955Cys. To our knowledge, this variant has not been reported in the literature. Of note, this variant has been found in the homozygous or compound heterozygous state in multiple individuals tested for polycystic kidney disease at PreventionGenetics. This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.