Submissions for variant NM_138694.4(PKHD1):c.983G>A (p.Arg328Gln)

gnomAD frequency: 0.00003  dbSNP: rs770494581

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000734720	SCV000862884	uncertain significance	not provided	2018-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004214	SCV001163072	likely pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001332901	SCV001525343	pathogenic	Polycystic kidney disease 4		criteria provided, single submitter	clinical testing
GeneDx	RCV000734720	SCV002559407	likely pathogenic	not provided	2023-12-08	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: 34536170, 24162162, 36065636)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003489848	SCV004241693	uncertain significance	not specified	2023-12-26	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.983G>A (p.Arg328Gln) results in a conservative amino acid change located in the IPT domain (IPR002909) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251218 control chromosomes. c.983G>A has been reported in trans along with different second pathogenic variants in individuals affected with Polycystic Kidney And Hepatic Disease and Stroke with features of polycystic renal dysplasia, respectively (Krall_2014,Bullich_2018, Kumar_2022, Ishiko_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, the variant showed WT-like transcript and did not affect splicing in HEK293T cells via a mini-gene assay (Ishiko_2022). The following publications have been ascertained in the context of this evaluation (PMID: 29801666, 34536170, 24162162, 36065636). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001004214	SCV004285300	pathogenic	Autosomal recessive polycystic kidney disease	2023-09-29	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 598347). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 34536170). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 24162162, 34536170). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 328 of the PKHD1 protein (p.Arg328Gln). This variant is present in population databases (rs770494581, gnomAD 0.009%).