Submissions for variant NM_138694.4(PKHD1):c.5895dup (p.Leu1966fs)

gnomAD frequency: 0.00010  dbSNP: rs746838237

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000681917	SCV000229843	pathogenic	not provided	2016-08-05	criteria provided, single submitter	clinical testing
Invitae	RCV000177889	SCV000629927	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.Leu1966Thrfs*4) 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 (rs746838237, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15108281, 19940839, 24162162, 27225849). This variant is also known as 5896insA and 5895_5896insA. ClinVar contains an entry for this variant (Variation ID: 167486). For these reasons, this variant has been classified as Pathogenic.
Gharavi Laboratory, Columbia University	RCV000681917	SCV000809400	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000177889	SCV000918001	pathogenic	Autosomal recessive polycystic kidney disease	2018-02-02	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5895dupA (p.Leu1966ThrfsX4) 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 (eg. c.9319C>T, p.Arg3107X; c.9689delA, p.Asp3230fsX34; c.10637delT, p.Val3546fsX22). The variant allele was found at a frequency of 8.3e-05 in 276786 control chromosomes, which is lower than the maximum expected allele frequency for a pathogenic variant in this gene. c.5895dupA has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease and is a common pathogenic variant. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000177889	SCV001163038	pathogenic	Autosomal recessive polycystic kidney disease		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000177889	SCV001194028	pathogenic	Autosomal recessive polycystic kidney disease	2019-12-09	criteria provided, single submitter	clinical testing	NM_138694.3(PKHD1):c.5895dupA(L1966Tfs*4) is classified as pathogenic in the context of PKHD1-related autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 19940839, 15698423, 15805161, 12846734, 12506140 and 11919560. Classification of NM_138694.3(PKHD1):c.5895dupA(L1966Tfs*4) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Molecular Biology Laboratory, Fundació Puigvert	RCV000177889	SCV001425230	pathogenic	Autosomal recessive polycystic kidney disease	2020-02-01	criteria provided, single submitter	research
Laboratory of Molecular Genetics, Children's Memorial Health Institute	RCV000177889	SCV001434256	pathogenic	Autosomal recessive polycystic kidney disease	2020-09-25	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001261932	SCV001439275	pathogenic	Polycystic kidney disease 4	2020-10-13	criteria provided, single submitter	research	ACMG codes:PVS1, PM2, PM3
GeneDx	RCV000681917	SCV001784785	pathogenic	not provided	2022-01-10	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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26695994, 15108281, 11919560, 27225849, 24162162, 32574212, 30595564, 33282801, 31589614, 19940839)
Revvity Omics, Revvity	RCV001261932	SCV002018826	pathogenic	Polycystic kidney disease 4	2021-07-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001261932	SCV002767674	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. There is significant intrafamilial variation of severity (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 (v2) <0.01 for a recessive condition (23 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported in many patients with polycystic kidney disease (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in ClinVar. It has also been reported in multiple individuals with autosomal recessive polycystic kidney disease (PMID:15805161) (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV001261932	SCV002780055	pathogenic	Polycystic kidney disease 4	2022-05-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001261932	SCV004202223	pathogenic	Polycystic kidney disease 4	2023-10-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000177889	SCV002078065	pathogenic	Autosomal recessive polycystic kidney disease	2017-03-17	no assertion criteria provided	clinical testing