Submissions for variant NM_001009944.3(PKD1):c.6395T>G (p.Phe2132Cys)

gnomAD frequency: 0.00020  dbSNP: rs150154235

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498031	SCV000589515	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing	Reported with a second PKD1 variant in unrelated patients in published literature with renal cysts, with or without hepatic fibrosis; authors suggest the F2132 variant may be a hypomorphic allele (PMID: 31730820, 31317121, 36706243); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31317121, 26489027, 30847201, 31740684, 36706243, 31730820, 21694639)
Baylor Genetics	RCV001332656	SCV001525036	uncertain significance	Polycystic kidney disease 3 with or without polycystic liver disease	2020-01-02	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Athena Diagnostics	RCV001662486	SCV001879447	benign	not specified	2021-04-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004023328	SCV005005265	uncertain significance	Inborn genetic diseases	2024-02-05	criteria provided, single submitter	clinical testing	The c.6395T>G (p.F2132C) alteration is located in exon 15 (coding exon 15) of the PKD1 gene. This alteration results from a T to G substitution at nucleotide position 6395, causing the phenylalanine (F) at amino acid position 2132 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000498031	SCV005411219	uncertain significance	not provided	2024-06-13	criteria provided, single submitter	clinical testing	BS1, BP2, BP5, PS4_supporting
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292314	SCV001480602	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Phe2132Cys variant was identified in 1 of 6 proband chromosomes (frequency: 0.2) from individuals or families with autosomal dominant polycystic kidney disease (O'Brien 2012). It was also identified in dbSNP (ID: rs150154235) as "With Uncertain Significance allele", ClinVar (classified as uncertain significance by GeneDx) and the ADPKD Mutation Database (as likely pathogenic). The variant was not identified in the LOVD 3.0 or PKD1-LOVD databases. It was identified in control databases in 66 of 213056 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 25 of 14648 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant), Other in 1 of 5294 chromosomes (freq: 0.0002), Latino in 9 of 29454 chromosomes (freq: 0.0003), European in 26 of 90964 chromosomes (freq: 0.0003), Finnish in 2 of 19576 chromosomes (freq: 0.0001), and South Asian in 3 of 25438 chromosomes (freq: 0.0001), while it was not observed in the African or Ashkenazi Jewish populations. 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.Phe2132 residue is 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) 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. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003915351	SCV004728535	likely benign	PKD1-related disorder	2022-06-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).