Submissions for variant NM_138694.4(PKHD1):c.10219C>T (p.Gln3407Ter)

gnomAD frequency: 0.00001  dbSNP: rs781368899

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000627228	SCV000231864	pathogenic	not provided	2014-05-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000627228	SCV000748217	pathogenic	not provided	2023-04-17	criteria provided, single submitter	clinical testing	Nonsense 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 (gnomAD); This variant is associated with the following publications: (PMID: 28375157, 25525159, 15108281, 19176689, 16133180, 31589614, 32939031, 20460933)
Invitae	RCV000844922	SCV001204146	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln3407*) 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 (rs781368899, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with polycystic kidney disease (PMID: 15108281, 16133180). ClinVar contains an entry for this variant (Variation ID: 198314). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000844922	SCV001362928	pathogenic	Autosomal recessive polycystic kidney disease	2019-08-19	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.10219C>T (p.Gln3407X) 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 1.2e-05 in 250288 control chromosomes. c.10219C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (Bergmann_2004, Losekoot_2005, Adeva_2006, Christiane Fischer_2009, Becker_2010). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000844922	SCV001425424	pathogenic	Autosomal recessive polycystic kidney disease	2020-04-24	criteria provided, single submitter	clinical testing	This nonsense variant results in a premature stop codon in exon 61 likely leading to nonsense-mediated decay and lack of protein production. This variant has been reported in multiple patients with autosomal recessive polycystic kidney disease. PKHD1 c.10219C>T (rs781368899) is rare (<0.1%) in a large population dataset (gnomAD: 3/250288 total alleles; 0.001%; no homozygotes). Four submitters in ClinVar classify this variant as pathogenic or likely pathogenic. We consider this variant to be pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002267610	SCV001427129	pathogenic	Polycystic kidney disease 4	2022-06-24	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) 0115 - Variants in this gene are known to have variable expressivity. Significant intrafamilial variation of severity has been reported (GeneReviews). (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 <0.01 for a recessive condition (v2: 3 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD 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. It has been regarded as likely pathogenic and pathogenic by multiple submitters in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited (segregation analysis by external laboratory). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
MGZ Medical Genetics Center	RCV002267610	SCV002580449	pathogenic	Polycystic kidney disease 4	2021-10-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002267610	SCV002816785	pathogenic	Polycystic kidney disease 4	2021-08-02	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002267610	SCV004013961	pathogenic	Polycystic kidney disease 4	2022-10-24	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Baylor Genetics	RCV002267610	SCV004202253	pathogenic	Polycystic kidney disease 4	2023-10-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000627228	SCV004226785	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	PM2_supporting, PM3, PS4_moderate, PVS1
GenomeConnect, ClinGen	RCV000844922	SCV000986737	not provided	Autosomal recessive polycystic kidney disease		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 03/26/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Yale Center for Mendelian Genomics, Yale University	RCV000845132	SCV000987068	likely pathogenic	Autosomal dominant polycystic liver disease	2017-04-04	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000627228	SCV001932182	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000627228	SCV001954670	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000844922	SCV002075523	pathogenic	Autosomal recessive polycystic kidney disease	2017-08-31	no assertion criteria provided	clinical testing