Submissions for variant NM_138694.4(PKHD1):c.9689del (p.Asp3230fs)

gnomAD frequency: 0.00005  dbSNP: rs398124502

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790769	SCV000231428	pathogenic	not provided	2016-06-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179217	SCV000699888	pathogenic	Autosomal recessive polycystic kidney disease	2016-12-08	criteria provided, single submitter	clinical testing	Variant summary: The c.9689delA (p.Asp3230Valfs) variant in PKHD1 gene is a frameshift change that results in the loss of the 812 amino acids of the protein (~20%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is present in the large control population dataset of ExAC at a frequency 0.000066 (8/121318 chrs tested), predominantly in individuals of Latino descent (0.0005; 6/11506) which does not exceed the maximal expected frequency of a pathogenic allele (0.007) in this gene. The variant has been identified homozygously or in the compound heterozygous state in numerous affected individuals with severe presentation. It is listed as the most common fraimshift pathogenic variant in Spanish population. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179217	SCV000816470	pathogenic	Autosomal recessive polycystic kidney disease	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp3230Valfs*34) 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 (rs398124502, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with autosomal recessive polycystic kidney disease (PMID: 12846734, 15805161, 19940839, 24162162). ClinVar contains an entry for this variant (Variation ID: 96444). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000179217	SCV001163017	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Molecular Biology Laboratory, Fundació Puigvert	RCV000179217	SCV001425246	pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV001535900	SCV001752535	pathogenic	Polycystic kidney disease 4	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000790769	SCV001871155	pathogenic	not provided	2021-04-07	criteria provided, single submitter	clinical testing	Frameshift 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: 19940839, 24162162, 19914852, 12846734, 15805161, 33258288, 31589614, 19021639, 26721323, 25701400, 15696446, 15698423)
Revvity Omics, Revvity	RCV001535900	SCV002018833	pathogenic	Polycystic kidney disease 4	2021-10-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001535900	SCV004202211	pathogenic	Polycystic kidney disease 4	2024-03-25	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001535900	SCV005399868	pathogenic	Polycystic kidney disease 4	2024-10-08	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 intrafamilial 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 <0.01 (v2 and v3(non-v2): 26 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have previously been reported as pathogenic (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 (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV000179217	SCV002075538	pathogenic	Autosomal recessive polycystic kidney disease	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390781	SCV004119607	pathogenic	PKHD1-related disorder	2023-12-24	no assertion criteria provided	clinical testing	The PKHD1 c.9689delA variant is predicted to result in a frameshift and premature protein termination (p.Asp3230Valfs*34). This variant has been reported to be causative for autosomal recessive polycystic kidney disease (Rossetti et al. 2003. PubMed ID: 12846734; Krall et al. 2014. PubMed ID: 24162162). This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic.