Submissions for variant NM_138694.4(PKHD1):c.982C>T (p.Arg328Ter)

gnomAD frequency: 0.00001  dbSNP: rs398124503

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790671	SCV000226174	pathogenic	not provided	2013-09-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000174804	SCV000485566	likely pathogenic	Autosomal recessive polycystic kidney disease	2016-01-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000174804	SCV001163073	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000174804	SCV001362926	pathogenic	Autosomal recessive polycystic kidney disease	2021-09-18	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.982C>T (p.Arg328X) 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 2.8e-05 in 251214 control chromosomes. c.982C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (example, Bergmann_2003, Denamur_2010, Jung_2020). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000174804	SCV001578412	pathogenic	Autosomal recessive polycystic kidney disease	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg328*) 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 (rs398124503, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with polycystic kidney disease (PMID: 12506140, 19940839). ClinVar contains an entry for this variant (Variation ID: 96445). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001580453	SCV001810575	pathogenic	Polycystic kidney disease 4	2021-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001580453	SCV004202259	pathogenic	Polycystic kidney disease 4	2024-01-18	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001580453	SCV005086028	pathogenic	Polycystic kidney disease 4	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease; however, there are emerging reports of heterozygous carriers of PKHD1 variants developing liver cysts and nephrocalcinosis (PMID: 21945273). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant intrafamilial variability has been reported (PMID: 20301501). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (7 heterozygotes, 0 homozygotes). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in one homozygous individual with polycystic kidney disease (PMID: 12506140) and one individual with polycystic kidney disease in whom the zygosity is unclear (PMID: 35373060). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV000174804	SCV002083379	pathogenic	Autosomal recessive polycystic kidney disease	2018-09-13	no assertion criteria provided	clinical testing