ClinVar Miner

Submissions for variant NM_000297.4(PKD2):c.784G>A (p.Val262Met) (rs138132026)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000384588 SCV000341154 likely benign not specified 2016-05-18 criteria provided, single submitter clinical testing
Invitae RCV001088117 SCV001003931 benign Autosomal dominant polycystic kidney disease 2020-11-25 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000863295 SCV001145038 benign not provided 2019-06-13 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001157035 SCV001318581 uncertain significance Polycystic kidney disease 2 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292418 SCV001480847 benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD2 p.Val262Met variant was not identified in the literature nor was it identified in the LOVD 3.0 or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs138132026) as "With Likely benign allele", ClinVar (classified as likely benign by EGL Genetics), and in ADPKD Mutation Database (as Likely Neutral). The variant was identified by our laboratory in a patient with a co-occurring pathogenic PKD2 variant (c.642_643dup, p.Lys215Argfs*19), increasing the likelihood that the p.Val262Met variant does not have clinical significance. The variant was identified in control databases in 204 of 276782 chromosomes (2 homozygous) at a frequency of 0.0007, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 24022 chromosomes (freq: 0.0003), Other in 5 of 6464 chromosomes (freq: 0.0008), Latino in 22 of 34400 chromosomes (freq: 0.0006), European in 113 of 126320 chromosomes (freq: 0.0009), Ashkenazi Jewish in 4 of 10136 chromosomes (freq: 0.0004), Finnish in 5 of 25790 chromosomes (freq: 0.0002), and South Asian in 48 of 30780 chromosomes (freq: 0.002), while the variant was not observed in the East Asian population. The p.Val262 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, this variant meets our laboratory criteria to be classified as benign.

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