Submissions for variant NM_138694.4(PKHD1):c.9718C>T (p.Arg3240Ter)

gnomAD frequency: 0.00001  dbSNP: rs1057516577

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411085	SCV000485896	likely pathogenic	Autosomal recessive polycystic kidney disease	2016-02-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727620	SCV000854886	pathogenic	not provided	2018-02-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411085	SCV002051396	pathogenic	Autosomal recessive polycystic kidney disease	2021-12-27	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.9718C>T (p.Arg3240X) 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 8e-06 in 251230 control chromosomes (gnomAD). c.9718C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (Bergmann_2003, Bergmann_2005, Shuster_2019, Burgmaier_2021). 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. 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411085	SCV002231366	pathogenic	Autosomal recessive polycystic kidney disease	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3240*) 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 0.01%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 12506140, 30650191). ClinVar contains an entry for this variant (Variation ID: 370548). 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.
Baylor Genetics	RCV003463795	SCV004204595	pathogenic	Polycystic kidney disease 4	2024-01-18	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003463795	SCV005073887	pathogenic	Polycystic kidney disease 4		criteria provided, single submitter	clinical testing	The stop-gained variant c.9718C>T(p.Arg3240Ter) in the PKHD1 gene has been reported in the compound heterozygous state in multiple individuals affected with polycystic kidney disease (Bergmann et al., 2003; Bergmann et al., 2005). The variant has 0.0007% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Pathogenic/ Likely Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.
Fulgent Genetics, Fulgent Genetics	RCV003463795	SCV005670574	pathogenic	Polycystic kidney disease 4	2024-02-22	criteria provided, single submitter	clinical testing