Submissions for variant NM_001009944.3(PKD1):c.971G>T (p.Arg324Leu)

gnomAD frequency: 0.00351  dbSNP: rs199476099

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000008688	SCV000884320	benign	Polycystic kidney disease, adult type	2019-04-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000756490	SCV001150735	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BS1, BS2
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000008688	SCV001370129	uncertain significance	Polycystic kidney disease, adult type	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS1,PP3,PP4,BP6,BS2.
GeneDx	RCV000756490	SCV001791088	likely benign	not provided	2020-09-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10364515, 12662927, 27499327, 19759016, 21115670, 17582161)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003150927	SCV003934670	likely benign	not specified	2023-05-24	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.971G>T (p.Arg324Leu) results in a non-conservative amino acid change located in the PKD domain (IPR000601) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 190410 control chromosomes, predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing Polycystic Kidney Disease 1 phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.971G>T has been reported in the literature in individuals affected with Polycystic Kidney Disease however without strong evidence for segregation (examples: Thomas_1999, Carrera_2016, Mansilla_2021). At-least one of these reports classified the variant as benign (Carrera_ 2016). The following publications have been ascertained in the context of this evaluation (PMID: 31738409, 32512653, 10364515, 27499327, 19759016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after and classified the variant as benign/likely benign (n=3), uncertain significance (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003924816	SCV004751549	benign	PKD1-related disorder	2020-09-14	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV000008688	SCV000028897	pathogenic	Polycystic kidney disease, adult type	1999-07-01	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000008688	SCV001142453	uncertain significance	Polycystic kidney disease, adult type	2020-01-06	no assertion criteria provided	curation	NM_001009944.2:c.971G>T in the PKD1 gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. This variant has been detected in a individual with autosomal dominant polycystic kidney disease (PMID: 10364515). Benign computational verdict because benign predictions from DEOGEN2, EIGEN, FATHMM-MKL, PrimateAI and SIFT. As a dominant inheritance manner, a total of 626 allleles was detected in gnomAD database which is a evidence to against its pathogenicity, although the adult-onset should be considered. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP4, BP4.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292035	SCV001480652	benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg324Leu variant was identified in 6 of 720 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Thomas 1999, Hoefele 2011, Rossetti 2007). The variant was also identified in dbSNP (ID: rs199476099) as “With Pathogenic allele”, Clinvitae (classified as pathogenic by ClinVar), ClinVar (classified as pathogenic by OMIM), MutDB, ADPKD Mutation Database (classified as likely neutral), and PKD1-LOVD 3.0 (probably does not affect function). This variant was identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), the NHLBI GO Exome Sequencing Project in 17 of 7568 European American and in 1 of 3614 African American alleles, the genome Aggregation Database (beta, October 19th 2016) in 501 (1 homozygous) of 192856 chromosomes (freq. 0.003), the Exome Aggregation Consortium database (August 8th 2016) in 157 (1 homozygous) of 24970 chromosomes (freq. 0.006) in the following populations: European in 139 of 11896 chromosomes (freq. 0.01), Finnish in 9 of 402 chromosomes (freq. 0.02), Latino in 6 of 1292 chromosomes (freq. 0.004), African in 2 of 1452 chromosomes (freq. 0.001), Other in 1 of 204 chromosomes (freq. 0.005), increasing the likelihood this could be a low frequency benign variant. The p.Arg324 residue is not 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. In addition, the variant was identified with an unspecified co-occurring pathogenic variant increasing the likelihood that the p.Arg324Leu variant does not have clinical significance (Rossetti 2007). It was also identified in one individual from our lab in homozygous form, and with a co-occurring PKD2 pathogenic variant (c.1662G>A, p.Trp554X) increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign.
Genetic Services Laboratory, University of Chicago	RCV003150927	SCV003839852	likely benign	not specified	2022-11-03	no assertion criteria provided	clinical testing