Submissions for variant NM_001009944.3(PKD1):c.11249G>A (p.Arg3750Gln)

dbSNP: rs1327414405

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788943	SCV000928243	pathogenic	not provided	2019-02-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000788943	SCV001248131	pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001095597	SCV001251232	uncertain significance	Polycystic kidney disease, adult type	2020-02-05	criteria provided, single submitter	research	PM5, PP3, PP4, PP5
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254256	SCV001430296	likely pathogenic	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
GeneDx	RCV000788943	SCV002504109	likely pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27499327, 21115670, 22008521, 23431072, 31740684, 22508176, 33437033, 33454723, 35778421, 37231942, 36706243)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001095597	SCV003934686	pathogenic	Polycystic kidney disease, adult type	2023-05-26	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.11249G>A (p.Arg3750Gln) results in a conservative amino acid change located in the Polycystin domain (IPR046791) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247254 control chromosomes (i.e., 1 heterozygous carrier; gnomAD v2.1, exomes cohort). c.11249G>A has been reported in the literature in multiple individuals affected with Polycystic Kidney Disease 1 (e.g., Hoefele_2011, Yu_2022, Kurashige_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21115670, 24611717, 35778421). Six ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: 4 submitters classified the variant as pathogenic (n = 2) or likely pathogenic (n = 2), and two submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001095597	SCV004808079	uncertain significance	Polycystic kidney disease, adult type	2024-03-29	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292160	SCV001480761	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg3750Gln variant was identified in 5 of 1474 proband chromosomes (frequency: 0.003) from French individuals or families with ADPKD (Audrezet 2012, Bataille 2011). Three of the affected individuals carried the c.11249_11250delinsAA, while one affected individual carried the c.11249G>A variant, both with the p.Arg3750Gln consequence (Audrezet 2012, Bataille 2011). The variant was also identified in ADPKD Mutation Database (classified highly likely pathogenic), and was not identified in dbSNP, ClinVar, LOVD 3.0, and PKD1-LOVD. The variant was identified in control databases in 1 of 243168 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017), observed in the following population: Ashkenazi Jewish in 1 of 9768 chromosomes (freq: 0.0001); it was not observed in the African, Other, Latino, European Non-Finnish, East Asian, Finnish, and South Asian populations. The p.Arg3750 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.