Submissions for variant NM_138694.4(PKHD1):c.5768A>T (p.Gln1923Leu)

gnomAD frequency: 0.00057  dbSNP: rs150838488

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724484	SCV000229844	uncertain significance	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000274741	SCV000464079	uncertain significance	Autosomal recessive polycystic kidney disease	2017-04-27	criteria provided, single submitter	clinical testing	The PKHD1 c.5768A>T (p.Gln1923Leu) variant is a missense variant that has been reported in a compound heterozygous state in one patient with polycystic kidney disease (Bergmann et al. 2005). The p.Gln1923Leu variant was absent from 200 controls but is reported at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Gln1923Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000724484	SCV000616823	uncertain significance	not provided	2022-11-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15698423, 26489027, 34426522)
Invitae	RCV000274741	SCV000824937	likely benign	Autosomal recessive polycystic kidney disease	2024-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000274741	SCV000897294	uncertain significance	Autosomal recessive polycystic kidney disease	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000724484	SCV000927770	uncertain significance	not provided	2018-06-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844070	SCV002104075	uncertain significance	not specified	2022-02-16	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.5768A>T (p.Gln1923Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 257770 control chromosomes (gnomAD, publications), predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00072 vs 0.0071), allowing no conclusion about variant significance. c.5768A>T has been reported in the literature in individuals affected with Kidney Disease (Bergmann_2005, Nicolaou_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003947510	SCV004772020	uncertain significance	PKHD1-related disorder	2024-02-23	criteria provided, single submitter	clinical testing	The PKHD1 c.5768A>T variant is predicted to result in the amino acid substitution p.Gln1923Leu. This variant was reported, along with a second missense variant in the same gene, in an individual with polycystic kidney disease (Bergmann et al. 2005. PubMed ID: 15698423); however, in another study, this variant was not found to be significantly enriched in an affected patient population (Miko et al. 2021. PubMed ID: 34405919, supplementary data). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000274741	SCV001459374	uncertain significance	Autosomal recessive polycystic kidney disease	2017-11-21	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000724484	SCV001741154	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724484	SCV001972861	uncertain significance	not provided		no assertion criteria provided	clinical testing