Submissions for variant NM_138694.4(PKHD1):c.3118C>T (p.Arg1040Ter)

dbSNP: rs755183117

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001222497	SCV001394597	pathogenic	Autosomal recessive polycystic kidney disease	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1040*) 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 0.006%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 19940839). ClinVar contains an entry for this variant (Variation ID: 950724). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001222497	SCV001774750	pathogenic	Autosomal recessive polycystic kidney disease	2021-08-02	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.3118C>T (p.Arg1040X) 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 251332 control chromosomes (gnomAD). c.3118C>T has been reported in the literature in at least an individual (in compound heterozygosity) affected with Polycystic Kidney and Hepatic Disease and also in another individual affected with Von Meyenburg complexes, congenital hepatic fibrosis and HBeAg-negative chronic hepatitis B in heterozygosity (example: Denamur_2010, Li_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001780149	SCV002018825	pathogenic	Polycystic kidney disease 4	2022-07-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001780149	SCV002775679	pathogenic	Polycystic kidney disease 4	2021-10-06	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV001780149	SCV003928015	pathogenic	Polycystic kidney disease 4		criteria provided, single submitter	clinical testing	A Heterozygous Nonsense variant c.3118C>T in Exon 28 of the PKHD1 gene that results in the amino acid substitution p.Arg1040* was identified. The observed variant his novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (ClinVar id: 950724). This sequence change creates a premature translational stop signal (p.Arg1040*) 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. This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (Denamur E et al., 2010). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Baylor Genetics	RCV001780149	SCV004204789	pathogenic	Polycystic kidney disease 4	2022-06-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001222497	SCV002081004	pathogenic	Autosomal recessive polycystic kidney disease	2017-08-31	no assertion criteria provided	clinical testing