ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1385G>A (p.Arg462Gln)

dbSNP: rs376854895
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000081505 SCV000113436 likely benign not specified 2017-09-29 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000147348 SCV000194723 uncertain significance Microcephaly, seizures, and developmental delay 2013-11-26 criteria provided, single submitter clinical testing
GeneDx RCV000081505 SCV000514222 uncertain significance not specified 2017-06-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PNKP gene. The R462Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R462Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. A different missense variant at the same position (R462P) has been reported in Human Gene Mutation Database in association with a PNKP-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the R462Q variant is observed in 17/514 (3.3%) alleles from individuals of Latino background in the ExAC dataset, which is greater than expected for this disorder (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001081069 SCV000560523 benign Developmental and epileptic encephalopathy, 12 2024-01-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV002313782 SCV000847733 likely benign Inborn genetic diseases 2018-07-10 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Athena Diagnostics RCV000466734 SCV001145115 benign not provided 2018-10-16 criteria provided, single submitter clinical testing

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