NM_005859.5(PURA):c.691TTC[2] (p.Phe233del) AND PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Apr 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000169739.35

Allele description [Variation Report for NM_005859.5(PURA):c.691TTC[2] (p.Phe233del)]

NM_005859.5(PURA):c.691TTC[2] (p.Phe233del)

Gene:

PURA:purine rich element binding protein A [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

5q31.3

Genomic location:

Preferred name:

NM_005859.5(PURA):c.691TTC[2] (p.Phe233del)

HGVS:

NC_000005.10:g.140114872TTC[2]
NC_000005.9:g.139494456_139494458del
NG_041813.1:g.5750TTC[2]
NM_005859.5:c.690_692delCTT
NM_005859.5:c.691TTC[2]MANE SELECT
NP_005850.1:p.Phe233del
NC_000005.9:g.139494456_139494458del
NC_000005.9:g.139494456_139494458delCTT
NC_000005.9:g.139494457TTC[2]
NM_005859.4:c.697_699del
NM_005859.4:c.697_699delTTC
NM_005859.5:c.690_692delCTTMANE SELECT
NM_005859.5:c.697_699delMANE SELECT
p.F233del

Protein change:

F233del

Links:

OMIM: 600473.0008; dbSNP: rs786204835

NCBI 1000 Genomes Browser:

rs786204835

Molecular consequence:

NM_005859.5:c.691TTC[2] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Name:: PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome (NEDRIHF)
Synonyms:: NEURODEVELOPMENTAL DISORDER WITH NEONATAL RESPIRATORY INSUFFICIENCY, HYPOTONIA, AND FEEDING DIFFICULTIES
Identifiers:: MedGen: C4015357; Orphanet: 438216; OMIM: 616158

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000221281	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 25342064, 27148565
SCV000655473	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 16, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25342064, 27148565, 28492532
SCV000778188	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001319412	Division of Biology and Genetics, University of Brescia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001362467	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 27, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25342064, 29150892, 29097605, 28726809, 27148565 Citation Link,
SCV001601518	Clinical Genetics Department, Johns Hopkins All Children's Hospital	no assertion criteria provided	Pathogenic	de novo	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25342064, 29150892, 28726809, 27148565
SCV002019567	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003842107	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25342064, 25741868
SCV003921115	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29097605, 25342064, 25741868
SCV004809819	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Asian	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Caucasian	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Reijnders MRF, Leventer RJ, Lee BH, Baralle D, Selber P, Paciorkowski AR, Hunt D.

2017 Apr 27. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

PubMed [citation]

PMID:: 28448108

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000221281.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a 6-year-old girl (patient 4) with neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF; 616158), Hunt et al. (2014) identified a de novo heterozygous 3-bp deletion (c.697_699delTTC, NM_005859.4), resulting in the deletion of a highly conserved residue (Phe233del) in the Pur repeat III domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed.

Tanaka et al. (2015) identified a de novo heterozygous c.697_699delTTC mutation in a 6-month-old girl with NEDRIHF. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. Functional studies of the variant were not performed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000655473.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 189319). This variant has been observed in individual(s) with developmental delay, cortical visual impairment, and hypotonia (PMID: 25342064, 27148565). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.697_699del, results in the deletion of 1 amino acid(s) of the PURA protein (p.Phe233del), but otherwise preserves the integrity of the reading frame.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000778188.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Biology and Genetics, University of Brescia, SCV001319412.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing	PubMed (1)

Description

p.Phe233del was found in a patient with severe hypotonia, global developmental delay, Delayed myelination and Drooling this leadig the diagnosis of PURA syndrome.

Description

The Phe233del variant in PURA has been reported in 8 patients with autosomal dominat PURA syndrome, characterized by moderate to severe intellectual disability (ID) and several early-onset issues including motor delay, hypotonia, feeding difficulties, hyperthermia, hypersomnolence, hypoventilation/apneas, speech delay and abnormal nonepileptic movements. Other less common manifestations include congenital heart defects, skeletal, urogenital, ophthalmological, gastrointestinal, and endocrine abnormalities; soft skin was also described as well as craniofacial dysmorphism (Reijnders et al., 1993; Hunt et al., 2014; Tanaka et al., 2015; Reijnders et al., 2018; Lee et al., 2018). p.Phe233del falls in the third PUR domain that mediate dimerization, and is predicted to cause local folding defects (Reijnders et al., 2018). Its putative pathogenicy was estimated through 3 different in silico prediction algorithms (SIFT, PROVEAN, MutPred Indel) that agreed to define p.phe233del as pathogenetic

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362467.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: PURA c.697_699delTTC (p.Phe233del) results in an in-frame deletion that is predicted to remove the third Phenylalanine in a run of three Phenylalanines located in the "presumed functional domain of PURA which is necessary for homodimerisation in crystallography studies (Hunt_2014). " The variant was absent in 251468 control chromosomes (gnomAD). c.697_699delTTC has been reported in the literature in multiple individuals affected with mental retardation and delays in cognitive development (Hunt_2014, Tanaka_2015, Strauss_2017, Lee_2018, Reijnders_2018). All the patients presented the mutation as a de novo occurrence. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Department, Johns Hopkins All Children's Hospital, SCV001601518.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002019567.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003842107.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been previously reported as de novo in similarly affected individuals (PMID: 25342064 ‚PMID: 29150892 ‚PMID: 29097605 ‚ PMID: 28726809, PMID: 27148565). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV003921115.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (3)

Description

A Heterozygous Inframe indel variant c.690_692delCTT in Exon 1 of the PURA gene that results in the amino acid substitution p.Phe231del was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (ClinVar ID: 189319). The Phe233del variant in PURA has been reported in 8 patients with autosomal dominat PURA syndrome, characterized by moderate to severe intellectual disability (ID) and several early-onset issues including motor delay, hypotonia, feeding difficulties, hyperthermia, hypersomnolence, hypoventilation/apneas, speech delay and abnormal nonepileptic movements. p.Phe233del falls in the third PUR domain that mediate dimerization, and is predicted to cause local folding defects (Reijnders MRF et al., 2018 and Hunt D et al., 2014). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004809819.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 4, 2025

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