Submissions for variant NM_138694.4(PKHD1):c.8411T>A (p.Met2804Lys)

gnomAD frequency: 0.00001  dbSNP: rs794727759

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790749	SCV000332131	likely pathogenic	not provided	2015-07-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000336528	SCV000800516	uncertain significance	Autosomal recessive polycystic kidney disease	2017-04-12	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics, Children's Memorial Health Institute	RCV000336528	SCV001434257	likely pathogenic	Autosomal recessive polycystic kidney disease	2020-05-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000336528	SCV001574613	likely pathogenic	Autosomal recessive polycystic kidney disease	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2804 of the PKHD1 protein (p.Met2804Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 20413436, 27752906). ClinVar contains an entry for this variant (Variation ID: 197958). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. 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.
Baylor Genetics	RCV003474935	SCV004202222	likely pathogenic	Polycystic kidney disease 4	2023-10-22	criteria provided, single submitter	clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV000336528	SCV001449398	likely pathogenic	Autosomal recessive polycystic kidney disease	2018-04-20	no assertion criteria provided	clinical testing	this individual was heterozygous for the c.8411T>A variant in the PKHD1 gene. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). It is listed in ClinVar as a likely pathogenic variant, without any supporting evidence provided. In silico analysis of pathogenicity (through Alamut Visual v2.8.1) is inconclusive regarding this change; SIFT predicts it to be likely pathogenic whereas PolyPhen2 and MutationTaster predicts this variant to be benign. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. Testing of parental specimens (see reports MG-18-02570 & MG-18-02571) indicates that two PKHD1 variants are in trans (on separate alleles). In light of this finding, the c.8411T>A variant has been reclassified as likely pathogenic, according to ACMG guidelines.