Submissions for variant NM_138694.4(PKHD1):c.353del (p.Ser118fs)

gnomAD frequency: 0.00003  dbSNP: rs398124483

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790659	SCV000231199	pathogenic	not provided	2012-10-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000179010	SCV000678070	likely pathogenic	Autosomal recessive polycystic kidney disease	2014-01-02	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000179010	SCV000745344	pathogenic	Autosomal recessive polycystic kidney disease	2017-03-17	criteria provided, single submitter	clinical testing
Invitae	RCV000179010	SCV000825136	pathogenic	Autosomal recessive polycystic kidney disease	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser118Ilefs*35) 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 (rs398124483, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive polycystic kidney disease (PMID: 15108281, 15805161, 16133180). ClinVar contains an entry for this variant (Variation ID: 96397). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000179010	SCV000915173	likely pathogenic	Autosomal recessive polycystic kidney disease	2016-09-28	criteria provided, single submitter	clinical testing	The PKHD1 c.353delG (p.Ser118IlefsTer35) variant results in a frameshift and is predicted to cause a premature termination of the protein. This variant has been reported in three studies and is found in a total of four individuals with autosomal recessive polycystic kidney disease, including three compound heterozygotes and one heterozygote in whom a second variant could not be identified (Bergmann et al. 2004. Sharp et al. 2005, Losekoot et al. 2005). The p.Ser118IlefsTer35 variant was absent from 300 controls but is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Ser118IlefsTer35 variant is classified as likely pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000179010	SCV001163083	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000179010	SCV001167629	pathogenic	Autosomal recessive polycystic kidney disease	2018-11-29	criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV000179010	SCV001425227	pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000790659	SCV001713352	pathogenic	not provided	2019-11-25	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000179010	SCV002768600	pathogenic	Autosomal recessive polycystic kidney disease	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 5 of 67). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic in patients with ARPKD (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple cases of ARPKD (ClinVar, HGMD, PMID: 15108281, PMID: 15805161, PMID: 16133180, PMID: 30650191). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics	RCV002505007	SCV002810518	pathogenic	Polycystic kidney disease 4	2022-04-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000790659	SCV003195101	pathogenic	not provided	2023-06-30	criteria provided, single submitter	clinical testing	Reported with a second variant (phase unknown) in unrelated patients with polycystic kidney disease (Losekoot et al., 2005; Sharp et al., 2005; Shuster et al., 2019); Frameshift 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 30650191, 15108281, 15805161, 33532864, 16133180)
Baylor Genetics	RCV002505007	SCV004204538	pathogenic	Polycystic kidney disease 4	2023-09-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002505007	SCV004238107	pathogenic	Polycystic kidney disease 4	2023-02-16	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000179010	SCV000734510	pathogenic	Autosomal recessive polycystic kidney disease		no assertion criteria provided	clinical testing
Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center	RCV001844806	SCV001876993	pathogenic	Autosomal dominant polycystic liver disease	2021-09-01	no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000790659	SCV002035757	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000179010	SCV002083414	pathogenic	Autosomal recessive polycystic kidney disease	2017-08-31	no assertion criteria provided	clinical testing