Submissions for variant NM_007254.4(PNKP):c.290A>G (p.Asn97Ser)

gnomAD frequency: 0.00019  dbSNP: rs140290151

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178284	SCV000230337	uncertain significance	not provided	2015-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810387	SCV000950583	uncertain significance	Developmental and epileptic encephalopathy, 12	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 97 of the PNKP protein (p.Asn97Ser). This variant is present in population databases (rs140290151, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. ClinVar contains an entry for this variant (Variation ID: 197287). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001129246	SCV001288755	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000178284	SCV002097438	uncertain significance	not provided	2024-10-23	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22508754)
Ambry Genetics	RCV002433778	SCV002746765	uncertain significance	Inborn genetic diseases	2021-05-04	criteria provided, single submitter	clinical testing	The c.290A>G (p.N97S) alteration is located in exon 4 (coding exon 3) of the PNKP gene. This alteration results from a A to G substitution at nucleotide position 290, causing the asparagine (N) at amino acid position 97 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485165	SCV002792428	uncertain significance	Charcot-Marie-Tooth disease type 2B2; Microcephaly, seizures, and developmental delay; Ataxia - oculomotor apraxia type 4	2022-02-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000178284	SCV003811229	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing