Submissions for variant NM_138694.4(PKHD1):c.3940del (p.Ser1314fs)

dbSNP: rs1057517273

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409843	SCV000487023	likely pathogenic	Autosomal recessive polycystic kidney disease	2016-09-27	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000788303	SCV000927361	likely pathogenic	not provided	2017-07-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000788303	SCV001168997	likely pathogenic	not provided	2019-11-15	criteria provided, single submitter	clinical testing	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 a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409843	SCV001364039	likely pathogenic	Autosomal recessive polycystic kidney disease	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.3940delA (p.Ser1314AlafsX2) 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. The variant allele was found at a frequency of 4e-06 in 250198 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3940delA in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000409843	SCV002222293	pathogenic	Autosomal recessive polycystic kidney disease	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1314Alafs*2) 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 (no rsID available, gnomAD 0.0009%). 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: 371441). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002488841	SCV002803533	likely pathogenic	Polycystic kidney disease 4	2022-05-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002488841	SCV004204685	pathogenic	Polycystic kidney disease 4	2023-04-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292409	SCV001480812	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKHD1 p.Ser1314Alafs*2 variant was not identified in the literature nor was it identified in the LOVD 3.0, or RWTH AAachen University ARPKD databases. The variant was identified in dbSNP (ID: rs1057517273) as "With Likely pathogenic allele", and ClinVar (classified as likely pathogenic by Counsyl). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3940del variant is predicted to cause a frameshift, which alters the protein amino acid sequence beginning at codon 1314 and leads to a premature stop codon at position 1315. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PKHD1 gene are an established mechanism of disease in ARPKD and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory criteria to be classified as pathogenic.
Natera, Inc.	RCV000409843	SCV002080972	likely pathogenic	Autosomal recessive polycystic kidney disease	2017-08-31	no assertion criteria provided	clinical testing