Submissions for variant NM_138694.4(PKHD1):c.1486C>T (p.Arg496Ter)

gnomAD frequency: 0.00066  dbSNP: rs137852949

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723837	SCV000331544	pathogenic	not provided	2015-09-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004330	SCV000699850	pathogenic	Autosomal recessive polycystic kidney disease	2016-08-25	criteria provided, single submitter	clinical testing	Variant summary: The PKHD1 c.1486C>T (p.Arg496X) variant results in a premature termination codon, predicted to cause a truncated or absent PKHD1 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 (e.g.c.9319C>T/p.Arg3107X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 69/121402 control chromosomes at a frequency of 0.0005684, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). Variant was primarily detected in Finnish European population in both controls and cases, and it was reported as a founder mutation for Finnish population. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Blueprint Genetics	RCV000723837	SCV000927414	pathogenic	not provided	2017-09-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004330	SCV001163065	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
GeneDx	RCV000723837	SCV001167698	pathogenic	not provided	2021-03-19	criteria provided, single submitter	clinical testing	Observed multiple times with a pathogenic variant in published literature and in a patient referred for genetic testing at GeneDx, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Gunay-Aygun et al., 2010); Reported heterozygous in a patient with polycystic liver disease (Besse et al., 2017); 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; This variant is associated with the following publications: (PMID: 22415584, 25525159, 12506140, 28375157, 15698423, 15200508, 20413436, 33123899)
Myriad Genetics, Inc.	RCV000004330	SCV001193870	pathogenic	Autosomal recessive polycystic kidney disease	2019-11-11	criteria provided, single submitter	clinical testing	NM_138694.3(PKHD1):c.1486C>T(R496*) is classified as pathogenic in the context of PKHD1-related autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 12506140 and 15698423. Classification of NM_138694.3(PKHD1):c.1486C>T(R496*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000723837	SCV001246968	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Invitae	RCV000004330	SCV001589609	pathogenic	Autosomal recessive polycystic kidney disease	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg496*) 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 present in population databases (rs137852949, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with autosomal recessive polycystic kidney disease (PMID: 12506140, 19914852, 22415584, 27225849). It is commonly reported in individuals of Finnish ancestry (PMID: 12506140). ClinVar contains an entry for this variant (Variation ID: 4114). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496252	SCV002812919	pathogenic	Polycystic kidney disease 4	2022-03-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002496252	SCV004202269	pathogenic	Polycystic kidney disease 4	2023-10-01	criteria provided, single submitter	clinical testing
OMIM	RCV000004330	SCV000024501	pathogenic	Autosomal recessive polycystic kidney disease	2003-01-01	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV000845135	SCV000987071	likely pathogenic	Autosomal dominant polycystic liver disease	2017-04-04	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000004330	SCV001142360	pathogenic	Autosomal recessive polycystic kidney disease	2020-01-06	no assertion criteria provided	curation	NM_138694.3:c.1486C>T in the PKHD1 gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. The PKHD1 c.1486C>T (p.Arg496*) variant results in a premature termination codon, predicted to cause a truncated or absent PKHD1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant has been reported in patients with autosomal recessive polycystic kidney disease, including six homozygotes, five compound heterozygotes (with V3471G and D2761Y) (PMID: 12506140; 15698423). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3_Strong, PP4.
Natera, Inc.	RCV000004330	SCV002081076	pathogenic	Autosomal recessive polycystic kidney disease	2017-03-17	no assertion criteria provided	clinical testing