Submissions for variant NM_138694.4(PKHD1):c.1626_1629del (p.Leu543fs)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387001	SCV001587470	pathogenic	Autosomal recessive polycystic kidney disease	2022-04-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Leu543Glnfs*2) 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 (rs777295562, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 11919560). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 1624del4. ClinVar contains an entry for this variant (Variation ID: 1073873).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001387001	SCV002571036	pathogenic	Autosomal recessive polycystic kidney disease	2022-07-05	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.1626_1629delACTT (p.Leu543GlnfsX2) 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.This variant is also known as 1624del4. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250886 control chromosomes (gnomAD). c.1626_1629delACTT has been reported in the literature in multiple compound heterozygous individuals affected with Polycystic Kidney And Hepatic Disease (examples: Gunay-Aygun_2010 and Ward_2002). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003473974	SCV004202204	pathogenic	Polycystic kidney disease 4	2023-10-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001387001	SCV002081071	pathogenic	Autosomal recessive polycystic kidney disease	2017-08-31	no assertion criteria provided	clinical testing

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