Submissions for variant NM_138694.4(PKHD1):c.2167C>T (p.Arg723Cys)

gnomAD frequency: 0.00001  dbSNP: rs794727366

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176334	SCV000227969	uncertain significance	not provided	2014-11-23	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272158	SCV002557534	uncertain significance	Polycystic kidney disease 4	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 22). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (384 heterozygotes, 4 homozygotes). (N) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity (ClinVar, PMID: 25646624, 27225849). (N) 0808 - Previous reports of pathogenicity are conflicting (ClinVar, PMID: 19914852, 29956005). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1102 - Strong phenotype match. (P) 1206 - Variant is paternally inherited. (N)
Revvity Omics, Revvity	RCV002272158	SCV003808422	uncertain significance	Polycystic kidney disease 4	2020-04-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000176334	SCV003921309	uncertain significance	not provided	2022-10-25	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; This variant is associated with the following publications: (PMID: 29956005, 19914852)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317127	SCV004020380	uncertain significance	not specified	2023-06-26	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.2167C>T (p.Arg723Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251212 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2167C>T has been reported in the literature in individuals affected with autosomal recessive polycystic kidney disease (examples: Gunay-Aygun_2010 and Szabo_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19914852, 29956005). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV002272158	SCV004204612	likely pathogenic	Polycystic kidney disease 4	2023-07-06	criteria provided, single submitter	clinical testing
Invitae	RCV003502520	SCV004263938	likely pathogenic	Autosomal recessive polycystic kidney disease	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 723 of the PKHD1 protein (p.Arg723Cys). This variant is present in population databases (rs794727366, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 19914852, 29956005). 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: 195701). 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 with a negative predictive value of 95%. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV002272158	SCV005042787	uncertain significance	Polycystic kidney disease 4		criteria provided, single submitter	clinical testing	The missense c.2167C>T p.Arg723Cys variant in PKHD1 gene has been reported previously in both homozygous and compound heterozygous state in individuals affected with autosomal recessive polycystic kidney disease Sathyan et al. 2021. The p.Arg723Cys variant is reported with an allele frequency of 0.0004% in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance multiple submissions. The amino acid change p.Arg723Cys in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 723 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Additional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS.