Submissions for variant NM_001009944.3(PKD1):c.5611G>A (p.Ala1871Thr)

gnomAD frequency: 0.00389  dbSNP: rs144137200

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003891871	SCV000305754	benign	PKD1-related condition	2019-06-22	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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999767	SCV000604753	benign	Polycystic kidney disease, adult type	2019-09-25	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000755337	SCV001144991	benign	not provided	2019-02-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000755337	SCV001816747	likely benign	not provided	2021-02-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17582161, 22608885, 30647506)
Fulgent Genetics, Fulgent Genetics	RCV000999767	SCV002809274	likely benign	Polycystic kidney disease, adult type	2022-04-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000755337	SCV002822249	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PKD1: BP4, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292134	SCV001480659	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Ala1871Thr variant was identified in 2 of 460 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD, being classified as a polymorphism/likely neutral (Rossetti 2007, Rossetti 2012, Tan 2009, Tan 2014). The variant was identified in dbSNP (ID: rs144137200) as “With Likely benign allele”, Clinvitae and ClinVar (classification likely benign, submitter Prevention Genetics), and the ADPKD Mutation Database (classification likely neutral); but was not identified in GeneInsight-COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was also identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002), HAPMAP-EUR in 3 of 1006 chromosomes (frequency: 0.003)/-AMR in 3 of 694 chromosomes (frequency: 0.0043)/-SAS in 2 of 978 chromosomes (frequency: 0.002), the NHLBI GO Exome Sequencing Project in 49 of 8560 European American alleles (freq. 0.006) and in 6 of 4374 African American alleles (freq. 0.001), the genome Aggregation Database (beta, October 19th 2016) in 1142 (4 homozygous) of 272522 chromosomes (freq. 0.004) and in the Exome Aggregation Consortium database (August 8th 2016) 485 (4 homozygous) of 104730 chromosomes (freq. 0.0046) in the following populations: European (Non-Finnish) in 364 of 57774 chromosomes (freq. 006), South Asian in 84 of 15042 chromosomes (freq. 006), Other in 4 of 732 chromosomes (freq. 006), Latino in 20 of 10302 chromosomes (freq. 002), African in 10 of 8320 chromosomes (freq. 001), and in European (Finnish) in 3 of 4634 chromosomes (freq. 0006); but was not seen in East Asian; increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala1871 residue is not conserved in mammals and 4 out of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000755337	SCV001799509	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000244459	SCV001930865	benign	not specified		no assertion criteria provided	clinical testing