Submissions for variant NM_007254.4(PNKP):c.416G>A (p.Arg139His)

gnomAD frequency: 0.00185  dbSNP: rs34472250

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001815201	SCV000194733	likely benign	not specified	2020-04-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000433486	SCV000203321	uncertain significance	not provided	2017-12-14	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000433486	SCV000511621	uncertain significance	not provided	2016-09-28	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000433486	SCV000514214	likely benign	not provided	2021-04-15	criteria provided, single submitter	clinical testing
Invitae	RCV001086537	SCV000560526	benign	Developmental and epileptic encephalopathy, 12	2024-01-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515248	SCV000611499	uncertain significance	Microcephaly, seizures, and developmental delay; Ataxia - oculomotor apraxia type 4	2017-05-23	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000433486	SCV000614683	likely benign	not provided	2018-10-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312656	SCV000847273	uncertain significance	Inborn genetic diseases	2019-02-08	criteria provided, single submitter	clinical testing	The p.R139H variant (also known as c.416G>A), located in coding exon 3 of the PNKP gene, results from a G to A substitution at nucleotide position 416. The arginine at codon 139 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000515248	SCV000898887	uncertain significance	Microcephaly, seizures, and developmental delay; Ataxia - oculomotor apraxia type 4	2018-10-24	criteria provided, single submitter	clinical testing	PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-50368466-C-T). This variant is present in ClinVar (Variation ID:159794). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000433486	SCV001151998	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PNKP: BP4, BS2
Illumina Laboratory Services, Illumina	RCV000147358	SCV001288754	likely benign	Microcephaly, seizures, and developmental delay	2018-01-12	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000433486	SCV001713023	uncertain significance	not provided	2020-04-15	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224167	SCV003920335	likely benign	Charcot-Marie-Tooth disease type 2B2; Microcephaly, seizures, and developmental delay; Ataxia - oculomotor apraxia type 4	2021-11-11	criteria provided, single submitter	clinical testing	PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-50368466-C-T). This variant is present in ClinVar (Variation ID:159794). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001815201	SCV003933878	likely benign	not specified	2023-05-10	criteria provided, single submitter	clinical testing	Variant summary: PNKP c.416G>A (p.Arg139His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251392 control chromosomes in the gnomAD database, including 2 homozygotes. To our knowledge, c.416G>A has not been reported in the literature in individuals affected with PNKP-Related Disorders and no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23833122, 34009545). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS (n=6), likely benign (n=6), benign (n=1)). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003927442	SCV004746961	likely benign	PNKP-related condition	2019-12-27	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000147358	SCV000238400	uncertain significance	Microcephaly, seizures, and developmental delay	2014-12-12	no assertion criteria provided	research	The heterozygous variant (c.416G>A; p.Arg139His) in the PNKP gene observed in this patient has not been associated with disease. It occurs at low frequencies in control population (0.2% in ExAC) and a second rare variant was not observed on the other allele. This variant is considered a variant of unknown significance.