Submissions for variant NM_001009944.3(PKD1):c.8713G>A (p.Val2905Ile)

gnomAD frequency: 0.00182  dbSNP: rs147788838

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000245081	SCV000305803	likely benign	not specified		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000992611	SCV001145018	benign	not provided	2019-01-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001284890	SCV001470986	uncertain significance	Polycystic kidney disease, adult type	2020-02-26	criteria provided, single submitter	clinical testing	The PKD1 c.8713G>A; p.Val2905Ile variant (rs147788838) is reported in the literature as a benign polymorphism (Rossetti 2001). This variant is also reported in ClinVar (Variation ID: 257028), and is found in the general population with an overall allele frequency of 0.17% (457/270176 alleles, including a single homozygote) in the Genome Aggregation Database. The valine at codon 2905 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Val2905Ile variant is uncertain at this time. References: Rossetti S et al. Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet. 2001 Jan;68(1):46-63.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001291904	SCV000592827	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Val2905Ile variant was identified as a polymorphism in the literature in a cohort of 131 patients with ADPKD however frequency information was not reported (Rossetti 2001). The variant was also identified in dbSNP (ID: rs147788838) as “NA”, and the ADPKD Mutation Database (classification “likely neutral”) but not in Clinvitae, ClinVar, GeneInsight COGR, PKD1-LOVD, or PKD1-LOVD 3.0 databases. The variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.0014); HAPMAP populations: AMR in 1 of 694 chromosomes (frequency: 0.0014), EUR in 5 of 1006 chromosomes (frequency: 0.005), and AFR in 1 of 1322 chromosomes (frequency: 0.0008); the NHLBI GO Exome Sequencing Project in 22 of 8316 European American alleles and in 4 of 4202 African American alleles; and in the Exome Aggregation Consortium database (March 14, 2016): 30 of 11356 alleles (frequency: 0.0026) in a Latino population, in 129 of 61572 alleles (1 homozygous, frequency: 0.0021) from a European (Non-Finnish) population, in 1 of 8386 alleles (frequency: 0.0001) from a East Asian population, in 6 of 8310 alleles (frequency: 0.0007) from an African population, in 3 of 16374 alleles (frequency: 0.0002) from a population of South Asian and in 2 of 6556 alleles (frequency: 0.0003) from a population of European (Finnish) individuals; it was not seen in “Other” population. The p.Val2905 residue is not conserved in mammals and the variant amino acid Ile is present in dog, increasing the likelihood that this variant does not have clinical significance. 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. This variant was identified in our laboratory in one individual with ADPKD and a co-occurring pathogenic variant in PKD1 (c.160_166dup, p.Leu56ProfsX60), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information this variant is classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000992611	SCV001931362	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000992611	SCV001975549	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000992611	SCV002036119	likely benign	not provided		no assertion criteria provided	clinical testing