Submissions for variant NM_000297.4(PKD2):c.2420G>A (p.Arg807Gln)

gnomAD frequency: 0.00312  dbSNP: rs147654263

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204608	SCV000260370	benign	Autosomal dominant polycystic kidney disease	2024-01-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000244886	SCV000303533	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001001908	SCV000451564	likely benign	Polycystic kidney disease 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000434759	SCV000511521	benign	not provided	2017-01-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000434759	SCV000514123	likely benign	not provided	2020-08-17	criteria provided, single submitter	clinical testing	Identified in a family with polycystic kidney disease (Magistroni et al., 2003); however, additional reports classify R807Q as indeterminate (Rossetti et al., 2007; Neumann et al., 2013); Functional study showed R807Q had no affect on the coiled-coil domain and interaction, and variant was classified as likely polymorphism (Giamarchi et al., 2010).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23300259, 22863349, 17582161, 20168298, 12707387, 26692149)
Eurofins Ntd Llc (ga)	RCV000244886	SCV000708717	benign	not specified	2017-06-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001908	SCV001159661	benign	Polycystic kidney disease 2	2018-12-30	criteria provided, single submitter	clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV000204608	SCV001430171	likely benign	Autosomal dominant polycystic kidney disease	2019-01-01	criteria provided, single submitter	research
Athena Diagnostics	RCV000244886	SCV001475372	benign	not specified	2019-10-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001001908	SCV002812628	likely benign	Polycystic kidney disease 2	2022-04-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292081	SCV001480821	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Arg807Gln variant was identified in 6 of 3926 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Magistroni 2003, Robinson 2012, Neumann 2013, Rossetti 2007, Rossetti 2012). The variant was also identified in the following databases: dbSNP (ID: rs147654263) as “With other allele”, ClinVar (classified as benign by Invitae and Children Mercy hospital; as likely benign by Prevention Genetics and Illumina; and as uncertain significance by GeneDx), LOVD 3.0 (1x, reported as "does not affect protein”), ADPKD Mutation Database (as likely neutral). The variant was not identified in PKD1-LOVD database. The variant was identified in control databases in 875 (4 homozygous) of 276852 chromosomes at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was observed in the following populations: African in 9 of 24032 chromosomes (freq. 0.0004), Other in 27 of 6462 chromosomes (freq. 0.004), Latino in 70 of 34396 chromosomes (freq. 0.002), European in 289 (1 homozygous) of 126416 chromosomes (freq. 0.002), Ashkenazi Jewish in 47 of 10138 chromosomes (freq. 0.005), East Asian in 1 of 18838 chromosomes (freq. 0.00005), Finnish in 431 (3 homozygous) of 25788 chromosomes (freq. 0.02), and South Asian in 1 of 30782 chromosomes (freq. 0.00003). The p.Arg807Gln residue is 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. A functional study showed R807Q had no effect on the coiled-coil domain; the variant was identified as likely polymorphism (Giamarchi 2010). In summary, based on the above information this variant meets our laboratory criteria to be classified as benign.