Submissions for variant NM_001009944.3(PKD1):c.7642G>C (p.Glu2548Gln)

gnomAD frequency: 0.02881  dbSNP: rs28369051

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000243935	SCV000305777	likely benign	not specified		criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000712650	SCV000843168	benign	not provided	2017-10-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001570	SCV001158958	benign	Polycystic kidney disease, adult type	2020-06-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000712650	SCV001884697	benign	not provided	2019-09-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10577909, 17574468, 22008521, 22383692)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291875	SCV000592806	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Glu2548Gln variant was identified in 3 of 604 proband chromosomes (frequency: 0.005) from individuals or families with AKPKD, and was not identified in 200 control chromosomes from healthy individuals (Bataille_2011, Rossetti_2012, Watnick_1999). The variant was also identified in dbSNP (ID: rs rs28369051) with no allele association indicated and listed in 1000 Genomes Project in 192 of 5013 chromosomes (frequency: 0.0383), in NHLBI GO Exome Sequencing Project (ESP) in 2 of 8130 European American (frequency: 0.0002) and 303 in 4042 African American alleles (frequency: 0.075). The variant is also identified in The Exome Aggregation Consortium (ExAC) database (released Mar 14, 2016) in 541 of 500090 chromosomes (frequency: 0.011) of which 30 homozygotes are of African ethnicity increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. Furthermore, the variant is listed in GeneInsight COGR database by LMM 1x as benign, in MutDB 1x as a polymorphism, and in ARPKD database 6x as likely neutral. The p. Glu2548residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. Furthermore, the variant amino acid (Gln) is present in dog, increasing the likelihood that this variant does not have clinical significance. 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. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000243935	SCV002035685	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000243935	SCV002037483	benign	not specified		no assertion criteria provided	clinical testing