ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.238C>T (p.Arg80Trp)

gnomAD frequency: 0.00008  dbSNP: rs551353498
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000712600 SCV000843117 benign not provided 2018-03-19 criteria provided, single submitter clinical testing
GeneDx RCV000712600 SCV002504667 likely benign not provided 2021-05-11 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
PreventionGenetics, part of Exact Sciences RCV003938053 SCV004748654 likely benign PKD1-related condition 2019-06-21 criteria provided, single submitter 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).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001292083 SCV001480849 benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Arg80Trp variant was not identified in the literature nor was it identified in the ClinVar, COGR, LOVD 3.0, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs551353498), ADPKD Mutation Database (classified indeterminate), and in control databases in 227 of 162048 chromosomes (7 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 4576 chromosomes (freq: 0.0002), Latino in 1 of 24584 chromosomes (freq: 0.00004), European Non-Finnish in 3 of 66780 chromosomes (freq: 0.00005), East Asian in 2 of 11550 chromosomes (freq: 0.0002), and South Asian in 220 (7 homozygous) of 22550 chromosomes (freq: 0.01), it was not observed in the African, Ashkenazi Jewish and European Finnish 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 variant was identified by our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.1391delT, p.Leu464GlnfsX94), increasing the likelihood that the p.Arg80Trp variant does not have clinical significance. The p.Arg80 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Trp 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 summary, based on the above information this variant meets our laboratory criteria to be classified as benign.

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