Submissions for variant NM_001009944.3(PKD1):c.12436G>A (p.Val4146Ile)

gnomAD frequency: 0.00312  dbSNP: rs148478410

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000243589	SCV000305694	likely benign	not specified		criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000576666	SCV000677397	benign	Polycystic kidney disease, adult type	2017-05-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000576666	SCV000885926	benign	Polycystic kidney disease, adult type	2019-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001545126	SCV001764395	likely benign	not provided	2021-03-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22383692, 10200984, 27843768, 27499327, 27401137, 11967008, 31488014)
CeGaT Center for Human Genetics Tuebingen	RCV001545126	SCV004033440	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PKD1: BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292522	SCV001480680	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Val4146Ile variant was identified in 8 of 1080 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD (Badenas 1999, Rossetti 2012, Rossetti 2002, Stekrova 2009). The variant was also identified in the following databases: dbSNP (ID: rs148478410) as “With Likely benign allele”, ClinVar (1x, as likely benign by Prevention Genetics), LOVD 3.0 (1x, with unknown effect, 1x as "Probably does not affect function"), ADPKD Mutation Database (as likely neutral). The variant was not identified in the PKD1-LOVD database. The variant was identified in control databases in 1211 of 271698 (5 homozygous) chromosomes at a frequency of 0.004457 in the following populations: African in 11 of 23782 chromosomes (freq. 0.00046), other in 41 of 6358 chromosomes (freq. 0.0064), Latino in 102 of 34238 chromosomes (freq. 0.003), European in 644 of 12418 (2 homozygous) chromosomes (freq. 0.005), Ashkenazi Jewish in 30 of 9890 chromosomes (freq. 0.003), East Asian in 1 of 18826 chromosomes (freq. 0.00005), Finnish in 117 of 25656 chromosomes (freq. 0.0045), and South Asian in 265 of 30530 (3 homozygous) chromosomes (freq. 0.0086), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic PKD1 variant (c.7864-1G>T) was identified in 1 individual with ADPKD in our laboratory, increasing the likelihood that p.Val4146Ile variant does not have clinical significance. The p.Val4146 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001545126	SCV001798147	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000243589	SCV001927612	benign	not specified		no assertion criteria provided	clinical testing