Submissions for variant NM_138694.4(PKHD1):c.1835A>G (p.His612Arg)

gnomAD frequency: 0.00009  dbSNP: rs369932370

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844757	SCV002104076	uncertain significance	not specified	2022-02-19	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.1835A>G (p.His612Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251160 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (4.4e-05 vs 0.0071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1835A>G in individuals affected with Polycystic Kidney And Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV002034737	SCV002108346	uncertain significance	Autosomal recessive polycystic kidney disease	2021-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 612 of the PKHD1 protein (p.His612Arg). This variant is present in population databases (rs369932370, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002482392	SCV002792435	uncertain significance	Polycystic kidney disease 4	2022-03-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401753	SCV004120248	uncertain significance	PKHD1-related disorder	2022-10-04	criteria provided, single submitter	clinical testing	The PKHD1 c.1835A>G variant is predicted to result in the amino acid substitution p.His612Arg. This variant has been reported in an individual with focal and segmental glomerulosclerosis (FSGS) (Wang et al. 2019. Table S4, Family S103.PubMed ID: 31308072). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51920386-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.