ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1381A>G (p.Asn461Asp) (rs775762473)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467950 SCV000549901 uncertain significance Early infantile epileptic encephalopathy 12 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 461 of the PNKP protein (p.Asn461Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. While this variant is not present in population databases (rs775762473), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a PNKP-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000483581 SCV000573314 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PNKP gene. The N461D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N461D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N461D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000719576 SCV000850445 uncertain significance History of neurodevelopmental disorder 2017-01-31 criteria provided, single submitter clinical testing Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000765462 SCV000896753 uncertain significance Early infantile epileptic encephalopathy 10; Ataxia-oculomotor apraxia 4 2018-10-31 criteria provided, single submitter clinical testing

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