Submissions for variant NM_138694.4(PKHD1):c.8011C>T (p.Arg2671Ter)

gnomAD frequency: 0.00001  dbSNP: rs137852947

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004328	SCV000942874	pathogenic	Autosomal recessive polycystic kidney disease	2023-10-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2671*) 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 (rs137852947, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with PKHD1-related conditions (PMID: 11919560, 26695994, 27225849, 28364132). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4112). 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	RCV000004328	SCV001163030	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004328	SCV001338100	pathogenic	Autosomal recessive polycystic kidney disease	2020-01-20	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.8011C>T (p.Arg2671X) 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 3.6e-05 in 251182 control chromosomes (gnomAD). c.8011C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (e.g. Ward_2002, Obeidova_2015, Melchionda_2016). 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 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV003137490	SCV003822907	pathogenic	Polycystic kidney disease 4	2022-03-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003137490	SCV005056329	pathogenic	Polycystic kidney disease 4	2024-01-20	criteria provided, single submitter	clinical testing
GeneDx	RCV004589495	SCV005078944	pathogenic	not provided	2023-12-05	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; This variant is associated with the following publications: (PMID: 25525159, 26695994, 12846734, 27225849, 28364132, 30650191, 32055034, 30275481, 34645488, 31328266, 16523049, 11919560, 35812281, 34536170)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003137490	SCV005087094	pathogenic	Polycystic kidney disease 4	2023-07-17	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, however there are emerging reports of heterozygous carriers of PKHD1 variants developing liver cysts and nephrocalcinosis (PMID: 21945273). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant intra-familial variability has been reported (PMID: 20301501). (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 (v2 and v3) <0.01 (11 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). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed as compound heterozygous with other PKHD1 variants in at least two families with ARPKD (PMIDs: 28364132, 11919560) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000004328	SCV000024499	pathogenic	Autosomal recessive polycystic kidney disease	2002-03-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000004328	SCV001459181	pathogenic	Autosomal recessive polycystic kidney disease	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748496	SCV005358471	pathogenic	PKHD1-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The PKHD1 c.8011C>T variant is predicted to result in premature protein termination (p.Arg2671*). This variant has been widely reported in individuals with autosomal recessive polycystic kidney disease (ARPKD) (see for example, Ebner et al. 2017. PubMed ID: 28364132; Ishiko et al. 2021. PubMed ID: 34536170). This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.