Submissions for variant NM_138694.4(PKHD1):c.11881C>T (p.Arg3961Ter)

gnomAD frequency: 0.00001  dbSNP: rs144193508

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000665966	SCV000891316	likely pathogenic	Autosomal recessive polycystic kidney disease	2017-09-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665966	SCV000950755	pathogenic	Autosomal recessive polycystic kidney disease	2024-04-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3961*) in the PKHD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 114 amino acid(s) of the PKHD1 protein. This variant is present in population databases (rs144193508, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 34536170; Invitae). 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. ClinVar contains an entry for this variant (Variation ID: 551016). This variant disrupts a region of the PKHD1 protein in which other variant(s) (p.Pro3968Leufs*70) have been observed in individuals with PKHD1-related conditions (PMID: 33940108). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001784237	SCV001163007	pathogenic	Polycystic kidney disease 4	2024-03-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001784237	SCV002024647	likely pathogenic	Polycystic kidney disease 4	2019-09-11	criteria provided, single submitter	clinical testing
GeneDx	RCV002245081	SCV002513635	likely pathogenic	not provided	2022-05-10	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 114 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published in an individual with PKHD1-related disease as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22034641, 30275481, 27535533)
Fulgent Genetics, Fulgent Genetics	RCV001784237	SCV005670466	likely pathogenic	Polycystic kidney disease 4	2024-03-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000665966	SCV000790187	uncertain significance	Autosomal recessive polycystic kidney disease	2017-03-07	flagged submission	clinical testing
Natera, Inc.	RCV000665966	SCV001455046	uncertain significance	Autosomal recessive polycystic kidney disease	2020-09-16	flagged submission	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001784237	SCV002769164	uncertain significance	Polycystic kidney disease 4	2020-05-21	flagged submission	clinical testing	A heterozygous nonsense variant, NM_138694.3(PKHD1):c.11881C>T, has been identified in exon 67 of 67 of the PKHD1 gene. The variant is predicted to result in a premature stop codon at position 3961 of the protein (NP_619639.3(PKHD1):p.(Arg3961*)). This variant is predicted to result in loss of protein function through truncation (although no known functional domains are affected). The variant is present in the gnomAD database at a frequency of 0.0024% (6 heterozygotes, 0 homozygotes). This variant has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE.