Submissions for variant NM_138694.4(PKHD1):c.5521G>A (p.Glu1841Lys)

dbSNP: rs913487671

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666915	SCV000791288	uncertain significance	Autosomal recessive polycystic kidney disease	2017-05-15	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000666915	SCV000965801	likely pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403545	SCV004122777	uncertain significance	not specified	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5521G>A (p.Glu1841Lys) 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 4e-06 in 251228 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5521G>A has been reported in the literature in a family with three siblings affected with spectrum of Caroli disease, Congenital hepatic fibrosis, Von Meyenburg complexes and authors reported this variant as a hypomorphic variant (example: Courcet_2015). This report does not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26385851). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000666915	SCV004514496	uncertain significance	Autosomal recessive polycystic kidney disease	2023-07-29	criteria provided, single submitter	clinical testing	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. 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: 551774). This missense change has been observed in individual(s) with PKHD1-related conditions (PMID: 26385851). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1841 of the PKHD1 protein (p.Glu1841Lys).