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

gnomAD frequency: 0.00112  dbSNP: rs115259839

Total submissions: 7

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: 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.