ClinVar Miner

Submissions for variant NM_000297.4(PKD2):c.2398A>C (p.Met800Leu) (rs2234917)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204140 SCV000260196 benign Autosomal dominant polycystic kidney disease 2020-11-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000253113 SCV000303532 benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000253113 SCV000520775 likely benign not specified 2016-03-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000584 SCV001157562 benign Polycystic kidney disease 2 2020-02-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001000584 SCV001316901 uncertain significance Polycystic kidney disease 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Genetics of Inherited Kidney Disorders Laboratory,Garvan Institute of Medical Research RCV000204140 SCV001430245 likely benign Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
Broad Institute Rare Disease Group, Broad Institute RCV001258257 SCV001435171 benign Joubert syndrome 7 criteria provided, single submitter research The heterozygous p.Met800Leu variant in PKD2 has been identified in 3 individuals with polycystic kidney disease, segregated with disease in 3 individuals from 1 family (PMID: 19936001), and has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant polycystic kidney disease.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292230 SCV001480574 benign Polycystic kidney disease no assertion criteria provided clinical testing The PKD2 p.Met800Leu variant was identified in 4 of 688 proband chromosomes (frequency: 0.006) from Spanish, Czech, American individuals or families with ADPKD (Gomez 2009, Reiterova 2002, Garcia-Gonzalez 2007, Rossetti 2012). Gomez et al (2009) identified the variant in a male proband and his two sisters all with terminal chronic kidney disease in their 50s, the variant was not present in his healthy daughters, however genetic testing of PKD1 was not performed in this family which would have been appropriate considering the severity of the phenotype. Reiterova et al (2002) identified the variant in a family with a generally mild course of disease (ESRD not before 65 years), the variant did not segregate with disease and co-occurred with a PKD2 frameshift variant (1339-1345INSGCAACAG, frameshift 448-472X). In addition the variant was identified in a family with ADPKD and was considered a polymorphism as it did not segregate with disease (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs2234917) as “With Benign allele”, Clinvitae (classification benign), ClinVar (classification benign, submitters Invitae and Prevention Genetics), ADPKD Mutation Database (classification likely neutral); and was not in GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was identified in the 1000 Genomes Project in 29 of 5000 chromosomes (frequency: 0.006), HAPMAP-SAS in 10 of 978 chromosomes (frequency: 0.01), HAPMAP-AFR in 12 of 1322 chromosomes (frequency: 0.009), HAPMAP-AMR in 4 of 694 chromosomes (frequency: 0.006), the NHLBI GO Exome Sequencing Project in 24 of 8600 European American (frequency: 0.0028) and in 24 of 8600 African American alleles (frequency: 0.0075), and in the Exome Aggregation Consortium database (August 8th 2016) in 583 (4 homozygous) of 121146 chromosomes (freq. 0.005) in the following populations: South Asian in 193 of 16502 chromosomes (freq. 01), African in 86 of 10404 chromosomes (freq. 0.008), Other in 5 of 902 chromosomes (freq. 0.006), European (Non-Finnish) in 264 of 66630 chromosomes (freq. 004), and Latino in 29 of 11528 chromosomes (freq. 0.003), EFinnish in 6 of 6602 chromosomes (frequency: 0.0009), but was not seen in East Asian population, increasing the likelihood this could be a low frequency benign variant; however, we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Met800 residue is not conserved in mammals and and the variant amino acid Leucine is present in dog and chicken, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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, this variant meets our laboratory criteria to be classified as benign.

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