Submissions for variant NM_007254.4(PNKP):c.721G>T (p.Glu241Ter)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002037963	SCV002231271	pathogenic	Developmental and epileptic encephalopathy, 12	2023-05-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 1453676). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Glu241*) in the PNKP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PNKP are known to be pathogenic (PMID: 20118933, 25728773).
Fulgent Genetics, Fulgent Genetics	RCV002497869	SCV002776022	likely pathogenic	Charcot-Marie-Tooth disease type 2B2; Microcephaly, seizures, and developmental delay; Ataxia - oculomotor apraxia type 4	2022-03-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004579583	SCV005062091	pathogenic	PNKP-related disorder	2024-03-11	criteria provided, single submitter	clinical testing	Variant summary: PNKP c.721G>T (p.Glu241X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 250932 control chromosomes (gnomAD). To our knowledge, no occurrence of c.721G>T in individuals affected with PNKP-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1453676). Based on the evidence outlined above, the variant was classified as pathogenic.

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