Submissions for variant NM_001009944.3(PKD1):c.6916-9G>A

dbSNP: rs1567190244

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761330	SCV000891315	likely pathogenic	Polycystic kidney disease 3 with or without polycystic liver disease	2017-12-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001823163	SCV002072762	likely pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant results in utilization of an alternate splice acceptor site leading to a truncating frameshift (Rossetti et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 17582161, 34713645, 33454723, 10854095)
PreventionGenetics, part of Exact Sciences	RCV003392579	SCV004119556	pathogenic	PKD1-related condition	2022-12-16	criteria provided, single submitter	clinical testing	The PKD1 c.6916-9G>A variant is predicted to interfere with splicing. This variant has not been found in the general population. It has been reported in multiple unrelated patients with autosomal dominant polycystic kidney disease (ADPKD) (Carrera et al., 2016. PubMed ID: 27499327; Rossetti et al., 2007. PubMed ID: 17582161; http://pkdb.mayo.edu/). Of note, at PreventionGenetics, we have previously found this variant in the heterozygous state in multiple presumably unrelated patients tested for polycystic kidney disease. In summary, we classify this variant as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292354	SCV001480709	likely pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 c.6916-9G>A variant was identified in 6 of 1522 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD (Hwang 2016, Carrera 2016, Kinoshita 2016); but it was not identified in 280 healthy control chromosomes (Kinoshita 2016). The variant was also identified in LOVD 3.0 (1x, classified as "affects function"), in PKDB (1x as highly likely pathogenic from a Caucasian (Italy), ADPKD Mutation Database (listed with AA change as Arg2306fs10X and mutation type as SPLICE; with highly likely pathogenic prediction). The variant was not identified in dbSNP, ClinVar, GeneInsight-COGR, PKD1-LOVD, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. There are conflicting predictions reported in the literature for variant c.6916-9G>A: (as non- truncating with protein consequence of p.Gln2305fsx10 by Hwang 2016; as highly likely pathogenic in 3 unrelated patients with the AA change as p.Gln2305fsx10 by Carrera 2016; and as definitely pathogenic with mutation type as "typical splicing" by Kinoshita 2016). The c.6916-9G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.