Submissions for variant NM_138694.4(PKHD1):c.12142_12143inv (p.Gln4048Ter)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001574114	SCV001800869	uncertain significance	not provided	2023-09-06	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469406	SCV002766525	uncertain significance	not specified	2022-11-04	criteria provided, single submitter	clinical testing	Variant summary: PKHD1 c.12142_12143delinsTG (p.Gln4048X) 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. To our knowledge, no downstream truncating mutations have been reported with strong evidence of causality. The variant allele was found at a frequency of 0.00034 in 282370 control chromosomes. To our knowledge, no occurrence of c.12142_12143delinsTG in individuals affected with Polycystic Kidney And Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
Invitae	RCV002570799	SCV003284487	uncertain significance	Autosomal recessive polycystic kidney disease	2021-08-30	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the PKHD1 gene (p.Unknown). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acids of the PKHD1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PKHD1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003426178	SCV004117666	uncertain significance	PKHD1-related disorder	2024-02-19	criteria provided, single submitter	clinical testing	The PKHD1 c.12142_12143delinsTG variant is predicted to result in premature protein termination (p.Gln4048*). To our knowledge, this variant has not been reported in the literature. Two adjacent variants have been reported in cis in gnomAD (GRCh37, chr6-51483962-G-A; chr6-51483961-T-C), and if combined would result in c.12142_12143delinsTG (p.Gln4048*). This premature protein termination resulting from another nucleotide change, c.12142C>T, has been reported in the heterozygous state in a patient with polycystic liver disease, but the disease causing role was uncertain (Besse et al. 2017. PubMed ID: 28375157). Importantly, this nonsense variant occurs at the last exon of the gene and we are uncertain if this premature stop codon variant results in nonsense mediated decay (NMD) of the transcript. To our knowledge, no downstream (more 3') nonsense variants in this gene have been reported to be pathogenic in the literature (Human Gene Mutation Database). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.