Submissions for variant NM_001009944.3(PKD1):c.12460C>T (p.Arg4154Cys)

gnomAD frequency: 0.00178  dbSNP: rs115538130

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000989445	SCV001139771	benign	Polycystic kidney disease, adult type	2023-08-22	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001171322	SCV001328269	uncertain significance	Chronic kidney disease	2020-05-28	criteria provided, single submitter	research	PP3, PP5
GeneDx	RCV001664593	SCV001875326	likely benign	not provided	2021-01-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32723786, 31157564, 20981092, 10987650, 26139440)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292093	SCV001480883	likely benign	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Arg4154Cys variant was identified in 5 of 1254 proband chromosomes (frequency: 0.004) from French, Tunisian and Italian individuals or families with ADPKD and not identified in 300 control chromosomes from healthy individuals (Audrezet_2015_26139440, Carrera_2016_27499327, Perrichot_1999_10987650). In segregation studies, the variant co-occurred with pathogenic PKD1 variants (c.7108T.A (PKD1) p.Cys2370Ser (PKD1)/c.5873G.A (PKD1) p.Trp1958X (PKD1)/c.6727_6730del (PKD1) p.Gln2243AlafsX6) inherited from the probands’ affected parents, while unaffected parents were shown to carry this variant; increasing the likelihood the variant has no clinical significance (Audrezet_2015_26139440). In another proband, the variant co-occurred with a likely pathogenic PKD1 variant (c.9361G> A p.Glu3121Lys) (Carrera_2016_27499327). The p.Arg4154Cys variant was also found in 1 proband’s affected daughter, leading to the variant assessment of likely pathogenic; however, PKD1 was only partially screened, with exons 34 to 46 only being screened . (Perrichot_1999_10987650). The variant was also identified in dbSNP (ID: rs115538130) as “NA”, LOVD 3.0, ADPKD Mutation Database (classified likely pathogenic, based on Perrichot et al. (1999)), and was not identified in ClinVar, Clinvitae, COGR, and PKD1-LOVD. The variant was identified in control databases in 269 (6 homozygous) of 265106 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 127 (2 homozygous) of 23396 chromosomes (freq: 0.005), “Other” in 2 of 6220 chromosomes (freq: 0.0003), Latino in 29 (1 homozygous) of 33684 chromosomes (freq: 0.000861), European Non-Finnish in 32 of 119926 chromosomes (freq: 0.0003), East Asian in 8 of 18612 chromosomes (freq: 0.0004), and South Asian in 71 (3 homozygous) of 29734 chromosomes (freq: 0.002); it was \not observed in the Ashkenazi Jewish and European Finnish populations. The p.Arg4154 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant Cys may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of 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.
PreventionGenetics, part of Exact Sciences	RCV003918615	SCV004729450	likely benign	PKD1-related disorder	2022-07-16	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).