Submissions for variant NM_138694.4(PKHD1):c.2725C>T (p.Arg909Ter)

gnomAD frequency: 0.00001  dbSNP: rs727504089

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790818	SCV000228393	pathogenic	not provided	2013-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000176696	SCV000918010	pathogenic	Autosomal recessive polycystic kidney disease	2023-02-16	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.2725C>T (p.Arg909X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251142 control chromosomes (gnomAD). c.2725C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (examples: Liang_2020, Obeidova_2020, Ajiri_2022,Ishiko_2022). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000176696	SCV000937061	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg909*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 167491). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000176696	SCV001163053	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781495	SCV002018818	pathogenic	Polycystic kidney disease 4	2020-08-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001781495	SCV002060147	pathogenic	Polycystic kidney disease 4	2021-11-10	criteria provided, single submitter	clinical testing	NM_138694.3(PKHD1):c.2725C>T(R909*) is a nonsense variant classified as pathogenic in the context of autosomal recessive polycystic kidney disease, PKHD1-related. R909* has been observed in cases with relevant disease (PMID: 31730820, 32574212). Functional assessments of this variant are not available in the literature. R909* has not been observed in population frequency databases. In summary, NM_138694.3(PKHD1):c.2725C>T(R909*) is a nonsense variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
GeneDx	RCV000790818	SCV002759201	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32574212, 31730820)
Fulgent Genetics, Fulgent Genetics	RCV001781495	SCV002811538	pathogenic	Polycystic kidney disease 4	2021-10-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001781495	SCV004204664	pathogenic	Polycystic kidney disease 4	2023-05-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917507	SCV004728745	pathogenic	PKHD1-related disorder	2024-02-05	criteria provided, single submitter	clinical testing	The PKHD1 c.2725C>T variant is predicted to result in premature protein termination (p.Arg909*). This variant has been reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (Liang et al. 2019. PubMed ID: 31730820). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.