VCV000432233.46 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 432233 Accession: VCV000432233.46

Type and length

Duplication, 1 bp

Location

Cytogenetic: 5q31.3 5: 140114334-140114335 (GRCh38) [ NCBI UCSC ] 5: 139493919-139493920 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 20, 2017	Oct 20, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005859.5:c.159dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005850.1:p.Leu54fs	frameshift
NM_005859.4:c.159dupG
NC_000005.10:g.140114340dup
NC_000005.9:g.139493925dup
NG_041813.1:g.5218dup

... more HGVS ... less HGVS

Protein change

L54fs

Other names

NM_005859.4:c.159_160insG
p.Leu54AlafsX147

Canonical SPDI

NC_000005.10:140114334:GGGGGG:GGGGGGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA645372805 dbSNP: rs1554129040 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PURA		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	482	540

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 29, 2021	RCV000498606.29
Intellectual disability	Likely pathogenic (1)	no assertion criteria provided	-	RCV001003590.3
PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV001035879.12
PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation	Pathogenic (1)	criteria provided, single submitter	Nov 18, 2016	RCV000616762.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 18, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000712536.2 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447067.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Nystagmus (present) , Hypotonia (present) , Global developmental delay (present) , Gait ataxia (present) , Strabismus (present) , Polyneuropathy (present) , Abnormality of the kidney … (more) Nystagmus (present) , Hypotonia (present) , Global developmental delay (present) , Gait ataxia (present) , Strabismus (present) , Polyneuropathy (present) , Abnormality of the kidney (present) , Absent speech (present) , Macrocephaly (present) (less) Sex: female
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002058612.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:32581362 PMID:32581362 Comment: 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 … (more) 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. (less) Clinical Features: Cerebellar hemorrhage (present) , Global developmental delay (present) , Developmental regression (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , … (more) Cerebellar hemorrhage (present) , Global developmental delay (present) , Developmental regression (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Muscle weakness (present) , Seizure (present) , Delayed speech and language development (present) , Generalized hypotonia (present) , Seizure (present) (less)
Pathogenic (Nov 29, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000589940.5 First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Oct 25, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001199218.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 32581362 Comment: 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 … (more) 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.Leu54Alafs147) 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. (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805298.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Sep 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248354.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
Likely pathogenic (-)	no assertion criteria provided Method: research	Intellectual disability Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001161967.1 First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 1 Sex: male

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362

Text-mined citations for rs1554129040 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554129040 ...