Submissions for variant NM_001009944.3(PKD1):c.8440G>A (p.Gly2814Arg)

gnomAD frequency: 0.00642  dbSNP: rs149151043

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003891880	SCV000305796	benign	PKD1-related condition	2019-09-05	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999797	SCV000604695	benign	Polycystic kidney disease, adult type	2018-07-26	criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001254304	SCV001430255	likely benign	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
GeneDx	RCV001651142	SCV001869130	benign	not provided	2020-03-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17574468, 12007219, 24374109, 18837007)
Fulgent Genetics, Fulgent Genetics	RCV000999797	SCV002806633	likely benign	Polycystic kidney disease, adult type	2021-09-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001651142	SCV004142835	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PKD1: BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292047	SCV001480689	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Gly2814Arg variant was identified in 29 of 1202 proband chromosomes (frequency: 0.024) from individuals or families with ADPKD (Garcia-Gonzalez 2007, Inoue 2002, Rossetti 2001, Rossetti 2002, Rossetti 2012, Tan 2008). The variant was also identified in dbSNP (ID: rs149151043) as "With other allele ", ClinVar (classified as benign by ARUP and Prevention Genetics), LOVD 3.0 (2x as benign or with unknown effect), and in ADPKD Mutation Database (likely neutral). The variant was not identified in COGR, or PKD1-LOVD databases. The variant was identified in control databases in 1715 of 275482 chromosomes (7 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 34 of 23822 chromosomes (freq: 0.0014), Other in 43 of 6430 chromosomes (freq: 0.0066), Latino in 146 of 34410 chromosomes (freq: 0.004), European in 1016 of 125388 chromosomes (freq: 0.008), Ashkenazi Jewish in 4 of 10094 chromosomes (freq: 0.00039), East Asian in 9 of 18840 chromosomes (freq: 0.00047), Finnish in 458 of 25724 chromosomes (freq: 0.017), and South Asian in 5 of 30774 chromosomes (freq: 0.00016). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Gly2814 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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 addition, the variant was identified with a co-occurring pathogenic PKD1 or PKD2 variants (PKD1 p.Glu2810*, p.Ile3109fs*, c.7704-1G>T; and PKD2 p.Arg872*), increasing the likelihood that the p.Gly2814Arg variant does not have clinical significance (Garcia-Gonzalez 2007). 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 benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000252501	SCV001800362	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000252501	SCV001929462	benign	not specified		no assertion criteria provided	clinical testing