Submissions for variant NM_138694.4(PKHD1):c.10174C>T (p.Gln3392Ter)

gnomAD frequency: 0.00002  dbSNP: rs201082169

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578239	SCV000680337	pathogenic	Autosomal recessive polycystic kidney disease	2017-11-23	criteria provided, single submitter	clinical testing
Invitae	RCV000578239	SCV000833677	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln3392*) 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 (rs201082169, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with autosomal recessive polycystic kidney disease (PMID: 11919560, 16133180, 23582048, 26673778). ClinVar contains an entry for this variant (Variation ID: 488579). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002470913	SCV000893724	pathogenic	Polycystic kidney disease 4	2021-11-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000578239	SCV001163016	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001249102	SCV001422387	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001249102	SCV001825909	pathogenic	not provided	2022-08-19	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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11919560, 16523049, 25525159, 12925574, 26673778, 23582048, 14741187, 12506140, 15108277, 15698423, 16133180, 29956005, 30650191, 31589614, 33437033, 32359821, 25701400)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000578239	SCV002104080	pathogenic	Autosomal recessive polycystic kidney disease	2022-02-22	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.10174C>T (p.Gln3392X) 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 1.6e-05 in 248566 control chromosomes (gnomAD). c.10174C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Ward_2002, Bergmann_2004). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470913	SCV002768829	pathogenic	Polycystic kidney disease 4	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-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) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. (Decipher; PMIDs: 15108281, 16133180). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals diagnosed with autosomal recessive polycystic kidney disease, either in homozygous or compound heterozygous form (ClinVar; PMIDs: 15108281, 16133180, 16523049, 29956005). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003420014	SCV004118167	pathogenic	PKHD1-related disorder	2023-06-13	criteria provided, single submitter	clinical testing	The PKHD1 c.10174C>T variant is predicted to result in premature protein termination (p.Gln3392*). This variant has been reported multiple unrelated individuals with autosomal recessive polycystic kidney disease (Ward et al. 2002. PubMed ID: 11919560; Losekoot et al. 2005. PubMed ID: 16133180; Shuster et al. 2019. PubMed ID: 30650191). This variant is reported in 0.0036% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51524750-G-A). Nonsense variants in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV002470913	SCV004204033	pathogenic	Polycystic kidney disease 4	2023-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001249102	SCV004701704	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PKHD1: PVS1, PM3:Strong, PM2
Natera, Inc.	RCV000578239	SCV002075524	pathogenic	Autosomal recessive polycystic kidney disease	2017-03-17	no assertion criteria provided	clinical testing