ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.650C>G (p.Thr217Ser)

gnomAD frequency: 0.00112  dbSNP: rs115259839
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724589 SCV000232250 uncertain significance not provided 2016-05-10 criteria provided, single submitter clinical testing
GeneDx RCV000724589 SCV000242023 likely benign not provided 2020-10-20 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002317059 SCV000850941 likely benign Inborn genetic diseases 2021-05-28 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.
Invitae RCV001079223 SCV001002451 likely benign Developmental and epileptic encephalopathy, 12 2024-01-26 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001136203 SCV001296027 likely benign Microcephaly, seizures, and developmental delay 2018-01-13 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Revvity Omics, Revvity RCV000724589 SCV003811222 uncertain significance not provided 2022-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003398901 SCV004121902 uncertain significance not specified 2023-10-19 criteria provided, single submitter clinical testing Variant summary: PNKP c.650C>G (p.Thr217Ser) results in a conservative amino acid change located in the HAD-superfamily hydrolase,subfamily IIIA (IPR006549) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 250814 control chromosomes, predominantly at a frequency of 0.0036 within the African or African-American subpopulation in the gnomAD database. To our knowledge, no occurrence of c.650C>G in individuals affected with PNKP-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely benign (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.

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