Submissions for variant NM_001009944.3(PKD1):c.12826C>T (p.Arg4276Trp)

gnomAD frequency: 0.00335  dbSNP: rs114251396

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000989444	SCV000885956	likely benign	Polycystic kidney disease, adult type	2019-04-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000989444	SCV001139770	benign	Polycystic kidney disease, adult type	2023-08-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001288333	SCV001475353	benign	not specified	2020-08-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001706706	SCV001873339	benign	not provided	2020-10-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32398770, 30816285, 17582161, 22383692, 22008521, 10200984, 20981092, 23431072, 22995991, 22508176)
CeGaT Center for Human Genetics Tuebingen	RCV001706706	SCV002545723	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292264	SCV001480923	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg4276Trp variant was identified in 12 of 3064 proband chromosomes (frequency: 0.004) from French, Italian, Spanish, and North American individuals or families with ADPKD (with or without family history), and was not identified in 459 control chromosomes from healthy individuals (Audrézet 2012, Carrera 2016, Rossetti 2012, Bataille 2011, Badenas 1999). The variant was found to co-occur with several PKD1 pathogenic/indeterminate variants (PKD1: p.Leu56Argfs*15, IVS37-10C3A/S3673fsX3674, Asp3781_Val3782insGlu, PKD2: R878del) and or multiple variants (PKD1 A4091A-G, V4058, V4044, and L4136L-T, Rossetti 2007, Carrera 2016, Bataille 2011, Badenas 1999). Ball et al (2012) used a public software tool for genome interpretation and a public database of variant interpretations, to review 10 presumed healthy genomes, the variant was identified in one participant and classified as uncertain significance. The variant was also identified in dbSNP (ID: rs114251396) as “NA”, the ADPKD Mutation Database (classification indeterminate), and PKD1-LOVD 3.0 (classification possibly damaging), the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002), the NHLBI GO Exome Sequencing Project in 28 of 8154 European American alleles (frequency: 0.003), and in the Exome Aggregation Consortium database (August 8, 2016) in 378 (2 homozygous) of 58652 chromosomes (frequency: 0.0064) in the following populations: Finnish in 65 of 1942 chromosomes (frequency: 0.03), European (Non-Finnish) in 282 of 32154 chromosomes (frequency: 0.009), Other in 2 of 392 chromosomes (frequency: 0.005), Latino in 9 of 3938 chromosomes (frequency: 0.002), South Asian in 16 of 11214 chromosomes (frequency: 0.001), and African in 4 of 4308 chromosomes (frequency: 0.0009); but was not seen in the East Asian population. The p.Arg4276 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp 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 1 of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.