Submissions for variant NM_005859.5(PURA):c.159dup (p.Leu54fs)

dbSNP: rs1554129040

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498606	SCV000589940	pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 269 amino acids are lost and replaced with 146 incorrect amino acids.; Not observed in large population cohorts (Lek et al., 2016); Reported in a large cohort of individuals with rare disease, but clinical information is not provided (Turro et al., 2020); This variant is associated with the following publications: (PMID: 32581362)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000616762	SCV000712536	pathogenic	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation	2016-11-18	criteria provided, single submitter	clinical testing	The p.Leu54fs variant in PURA has not been previously reported in individuals wi th severe neonatal hypotonia-seizures-encephalopathy syndrome. Data from large p opulation studies is insufficient to assess the frequency of this variant. The p .Leu54fs variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 54 and leads to a premature terminatio n codon 147 amino acids downstream. This gene contains a single exon, so the alt ered transcript is more likely to escape nonsense mediated decay (NMD) and resul t in a truncated protein. Heterozygous truncating variants in the PURA gene are strongly associated with severe neonatal hypotonia-seizures-encephalopathy syndr ome, with the all causative variants reported to date occuring de novo. In summa ry, the p.Leu54fs variant meets criteria to be classified as pathogenic for seve re neonatal hypotonia-seizures-encephalopathy syndrome based on its predicted im pact to the protein.
Invitae	RCV001035879	SCV001199218	pathogenic	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome	2022-10-25	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 432233). This premature translational stop signal has been observed in individual(s) with clinical features of PURA-related conditions (PMID: 32581362). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu54Alafs*147) in the PURA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 269 amino acid(s) of the PURA protein. This variant disrupts a region of the PURA protein in which other variant(s) (p.Tyr240*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000498606	SCV001248354	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000498606	SCV001447067	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
3billion	RCV001035879	SCV002058612	pathogenic	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome	2022-01-03	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000432233, PMID:32581362). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001035879	SCV004805298	pathogenic	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome	2024-03-25	criteria provided, single submitter	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003590	SCV001161967	likely pathogenic	Intellectual disability		no assertion criteria provided	research