Submissions for variant NM_138694.4(PKHD1):c.370C>T (p.Arg124Ter)

gnomAD frequency: 0.00001  dbSNP: rs727504096

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179011	SCV000231200	pathogenic	not provided	2014-03-21	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626995	SCV000747698	pathogenic	Abnormal intrahepatic bile duct morphology	2017-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000796722	SCV000936247	pathogenic	Autosomal recessive polycystic kidney disease	2023-08-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 167499). This premature translational stop signal has been observed in individuals with polycystic kidney disease (PMID: 15805161, 27225849). This variant is present in population databases (rs727504096, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Arg124*) 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).
Baylor Genetics	RCV000796722	SCV001163082	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV000796722	SCV001425228	pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000796722	SCV001442776	pathogenic	Autosomal recessive polycystic kidney disease	2020-10-30	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.370C>T (p.Arg124X) 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 allele was found at a frequency of 8e-06 in 251434 control chromosomes (gnomAD). c.370C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Sharp_2005, Denamur_2010, Obeidova_2015, Melchionda_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV002287372	SCV002577796	pathogenic	Kidney disorder	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PP5
Baylor Genetics	RCV003474811	SCV004202230	pathogenic	Polycystic kidney disease 4	2023-10-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000796722	SCV002083413	pathogenic	Autosomal recessive polycystic kidney disease	2017-11-30	no assertion criteria provided	clinical testing