Submissions for variant NM_138694.4(PKHD1):c.10909C>T (p.Arg3637Cys)

gnomAD frequency: 0.00025  dbSNP: rs141349745

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082518	SCV000114560	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000671676	SCV000796674	uncertain significance	Autosomal recessive polycystic kidney disease	2017-12-28	criteria provided, single submitter	clinical testing
Invitae	RCV000671676	SCV000831087	uncertain significance	Autosomal recessive polycystic kidney disease	2021-08-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 3637 of the PKHD1 protein (p.Arg3637Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs141349745, ExAC 0.04%). This missense change has been observed in individual(s) with symptoms of polycystic kidney disease (PMID: 16523049). ClinVar contains an entry for this variant (Variation ID: 96368). 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: "Possibly Damaging"; 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.
Illumina Laboratory Services, Illumina	RCV000671676	SCV001321742	uncertain significance	Autosomal recessive polycystic kidney disease	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000082518	SCV001985425	uncertain significance	not provided	2021-04-29	criteria provided, single submitter	clinical testing	Observed in an unrelated patient with congenital hepatic fibrosis, kidney cysts, and kidney stones in the literature (Adeva et al., 2006); 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: 30260789, 16523049)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228213	SCV002511955	uncertain significance	not specified	2022-04-19	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.10909C>T (p.Arg3637Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 250884 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0002 vs 0.0071), allowing no conclusion about variant significance. c.10909C>T has been reported in the literature in at-least two individuals affected with features of Autosomal recessive polycystic kidney disease (example, Adeva_2006, Sag_2018). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003407465	SCV004113201	uncertain significance	PKHD1-related disorder	2023-05-16	criteria provided, single submitter	clinical testing	The PKHD1 c.10909C>T variant is predicted to result in the amino acid substitution p.Arg3637Cys. This variant has been reported in the homozygous state in an infant with cholestasis, acholic stool, and high gamma-glutamyltransferase (Sağ et al. 2018. PubMed ID: 30260789) as well as an individual with abnormal liver morphology in a cohort of individuals presenting with autosomal recessive polycystic kidney disease or congenital hepatic fibrosis (M200, Table 2, Adeva et al. 2006. PubMed ID: 16523049). This variant is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51524015-G-A). While we suspect this variant could be pathogenic, at this time we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000671676	SCV002075497	uncertain significance	Autosomal recessive polycystic kidney disease	2018-09-22	no assertion criteria provided	clinical testing