Submissions for variant NM_000297.4(PKD2):c.1445T>G (p.Phe482Cys)

gnomAD frequency: 0.00176  dbSNP: rs75762896

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080594	SCV000259367	benign	Autosomal dominant polycystic kidney disease	2024-01-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000244662	SCV000303527	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000244662	SCV000331226	benign	not specified	2015-08-03	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712679	SCV000843198	benign	not provided	2018-06-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001706	SCV001159282	benign	Polycystic kidney disease 2	2020-05-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001001706	SCV001429835	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000712679	SCV001782682	likely benign	not provided	2021-01-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32859249, 18257781, 27894351, 27884173, 18837007, 22995991, 22863349, 31349084)
CeGaT Center for Human Genetics Tuebingen	RCV000712679	SCV004152956	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	PKD2: PM5, BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292488	SCV001481081	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD2 p.Phe482Cys variant was identified in 7 of 954 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011, Dedoussis 2008, Edrees 2016, Robinson 2012, Rossetti 2012, Tan 2008). The variant was also identified in the following databases: dbSNP (ID: rs75762896) as With other allele, ClinVar (classified as benign by Invitae; as likely benign by Prevention), Clinvitae , LOVD 3.0, ADPKD Mutation Database (classified as likely neutral). The variant was not identified in the COGR, or PKD1-LOVD databases. The variant was identified in control databases in 548 of 277128 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 7 of 24034 chromosomes (freq: 0.0003), “Other” in 38 of 6462 chromosomes (freq: 0.01), Latino in 67 of 34416 chromosomes (freq: 0.002), EuropeanNon-Finnish in 302 of 126624 chromosomes (freq: 0.002), AshkenaziJewish in 102 of 10152 chromosomes (freq: 0.01), EuropeanFinnish in 3 of 25792 chromosomes (freq: 0.0001), and SouthAsian in 29 of 30782 chromosomes (freq: 0.001); it was not observed in the EastAsian population. The p.Phe482 residue is conserved in mammals but not in more distantly related 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified with a co-occurring pathogenic PKD1 variant (IVS21–2delAG), increasing the likelihood that the p.Phe482Cys variant does not have clinical significance (Dedoussis 2008). 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000712679	SCV001741368	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000712679	SCV001931098	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000712679	SCV002035754	likely benign	not provided		no assertion criteria provided	clinical testing