Submissions for variant NM_138694.4(PKHD1):c.1690C>T (p.Arg564Ter)

gnomAD frequency: 0.00001  dbSNP: rs765251347

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174805	SCV001338151	pathogenic	Autosomal recessive polycystic kidney disease	2020-02-10	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.1690C>T (p.Arg564X) 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 4e-06 in 251068 control chromosomes (gnomAD). c.1690C>T has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease (e.g. Denamur_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001174805	SCV001392194	pathogenic	Autosomal recessive polycystic kidney disease	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg564*) 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 (rs765251347, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 19940839, 27491411). ClinVar contains an entry for this variant (Variation ID: 917672). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471039	SCV002768023	pathogenic	Polycystic kidney disease 4	2021-05-06	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. (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) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least 10 NMD-predicted variants that have been identified in affected individuals (ClinVar; PMID: 19940839). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been shown to be compound heterozygous in at least 5 individuals with autosomal recessive polycystic kidney disease (ClinVar; PMIDs: 19940839, 27491411, 30650191). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002471039	SCV002790090	pathogenic	Polycystic kidney disease 4	2022-01-19	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001174805	SCV003922239	pathogenic	Autosomal recessive polycystic kidney disease	2023-05-02	criteria provided, single submitter	curation	The homozygous p.Arg564Ter variant in PKHD1 was identified by our study in one individual with renal dysplasia and Potter facies. The p.Arg564Ter variant in PKHD1 has been previously reported in 6 unrelated individuals with autosomal recessive polycystic kidney disease (PMID: 19940839, PMID: 27491411, PMID: 30650191, PMID: 34536170) but has been identified in 0.002% (1/41400) of African/African American chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs765251347). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 6 previously reported unrelated individuals (PMID: 19940839, PMID: 27491411, PMID: 30650191, PMID: 34536170), four were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 34536170, ClinVar Variation ID: 632491; PMID: 19940839, ClinVar Variation ID: 96387, 96444), which increases the likelihood that the p.Arg564Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 917672) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 564, which is predicted to lead to a truncated or absent protein. Loss of function of the PKHD1 gene is an established disease mechanism in autosomal recessive polycystic kidney disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive polycystic kidney disease. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong (Richards 2015).
Baylor Genetics	RCV002471039	SCV004204646	pathogenic	Polycystic kidney disease 4	2023-05-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001174805	SCV002081069	pathogenic	Autosomal recessive polycystic kidney disease	2017-08-31	no assertion criteria provided	clinical testing