There are 3 more families with similar phenotype
ClinVar Genomic variation as it relates to human health
NM_021222.3(PRUNE1):c.316G>A (p.Asp106Asn)
Germline
Classification
Help
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.
(13)
Help
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/Likely pathogenic
13
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_021222.3(PRUNE1):c.316G>A (p.Asp106Asn)
Variation ID: 402131 Accession: VCV000402131.46
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q21.3 1: 151018650 (GRCh38) [ NCBI UCSC ] 1: 150991126 (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 Apr 3, 2017 Oct 20, 2024 Mar 14, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_021222.3:c.316G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_067045.1:p.Asp106Asn missense NM_001303229.2:c.-212+746G>A intron variant NM_001303242.2:c.316G>A NP_001290171.1:p.Asp106Asn missense NM_001303243.2:c.57G>A NP_001290172.1:p.Ser19= synonymous NC_000001.11:g.151018650G>A NC_000001.10:g.150991126G>A NG_052875.1:g.15260G>A - Protein change
- D106N
- Other names
- -
- Canonical SPDI
- NC_000001.11:151018649:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| PRUNE1 | - | - |
GRCh38 GRCh37 |
119 | 132 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV000454333.2 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 14, 2024 | RCV000490535.21 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 17, 2021 | RCV001090402.30 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Abnormal brain morphology
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000537906.1
First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
There are 3 more families with similar phenotype
Geographic origin: Turkey
Tissue: Blood
|
|
|
Pathogenic
(May 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
Affected status: yes
Allele origin:
inherited
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000966201.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
Observed as a homozygote.
|
|
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Pathogenic
(Oct 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001251444.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
|
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Pathogenic
(May 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
Affected status: yes
Allele origin:
unknown
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251858.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
|
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Pathogenic
(Jan 16, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680349.2
First in ClinVar: Feb 08, 2018 Last updated: Aug 20, 2020 |
Observation 1:
Clinical Features:
Abnormal basal ganglia MRI signal intensity (present) , Dystonic disorder (present) , Epileptic encephalopathy (present) , Abnormal brainstem MRI signal intensity (present) , Spasticity (present) … (more)
Abnormal basal ganglia MRI signal intensity (present) , Dystonic disorder (present) , Epileptic encephalopathy (present) , Abnormal brainstem MRI signal intensity (present) , Spasticity (present) , Focal clonic seizure (present) , Global developmental delay (present) (less)
Sex: female
Tissue: blood
Observation 2:
Sex: female
Tissue: blood
Observation 3:
Sex: female
Tissue: blood
|
|
|
Pathogenic
(Jun 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762256.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Nystagmus (present) , Seizure (present) , Generalized hypotonia (present) , Neonatal hypotonia (present) , Myoclonus (present) , Drooling (present) , Hypokinesia (present) , Oculogyric crisis … (more)
Nystagmus (present) , Seizure (present) , Generalized hypotonia (present) , Neonatal hypotonia (present) , Myoclonus (present) , Drooling (present) , Hypokinesia (present) , Oculogyric crisis (present) (less)
Sex: male
|
|
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Pathogenic
(Jan 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059724.1
First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022 |
|
|
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Pathogenic
(Jan 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
Affected status: yes
Allele origin:
biparental
|
Provincial Medical Genetics Program of British Columbia, University of British Columbia
Accession: SCV002320834.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
Sex: male
|
|
|
Pathogenic
(Jan 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001576800.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with PRUNE1-related neurodevelopmental conditions (PMID: 26539891, 28334956, 29797509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 402131). This variant is present in population databases (rs773618224, ExAC 0.02%). This sequence change replaces aspartic acid with asparagine at codon 106 of the PRUNE1 protein (p.Asp106Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. (less)
|
|
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Pathogenic
(May 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245938.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047534.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.316G>A (p.Asp106Asn) in PRUNE1 gene has been reported to be homozygous in several individuals with syndromic intellectual disability (Karaca E et.al.,2015). Experimental … (more)
The missense variant c.316G>A (p.Asp106Asn) in PRUNE1 gene has been reported to be homozygous in several individuals with syndromic intellectual disability (Karaca E et.al.,2015). Experimental studies show that missense change affect PRUNE1 function (Zollo M et.al .,2017). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Asp106Asn variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.00005177% is reported in gnomAD. The amino acid Asp at position 106 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Dyskinesia (present) , Seizure (present) , CNS demyelination (present) , Peripheral demyelination (present) , Cerebral cortical atrophy (present) , Abnormal … (more)
Global developmental delay (present) , Dyskinesia (present) , Seizure (present) , CNS demyelination (present) , Peripheral demyelination (present) , Cerebral cortical atrophy (present) , Abnormal meningeal morphology (present) , Thin corpus callosum (present) (less)
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Pathogenic
(Mar 14, 2024)
|
criteria provided, single submitter
Method: research
|
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004801175.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Oct 21, 2022)
|
no assertion criteria provided
Method: literature only
|
NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, HYPOTONIA, AND VARIABLE BRAIN ANOMALIES
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000577901.3
First in ClinVar: May 27, 2017 Last updated: Oct 29, 2022 |
Comment on evidence:
In 2 unrelated patients (BAB3500 and BAB3737), each born of consanguineous Turkish parents, with neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; 617481), … (more)
In 2 unrelated patients (BAB3500 and BAB3737), each born of consanguineous Turkish parents, with neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; 617481), Karaca et al. (2015) identified a homozygous c.316G-A transition (c.316G-A, NM_021222) in the PRUNE1 gene, resulting in an asp106-to-asn (D106N) substitution at a conserved residue in the DHH catalytic domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Haplotype analysis suggested a founder effect. Functional studies of the variant and studies of patient cells were not performed. In 2 sibs (family C) with NMIHBA, Zollo et al. (2017) identified a homozygous D106N mutation in the PRUNE1 gene. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was found in 5 heterozygotes in the ExAC database. In a Caucasian patient (patient 2), born to consanguineous parents, with NMIHBA, Imagawa et al. (2018) identified homozygosity for the D106N substitution in the PRUNE1 gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was found in the carrier state in the parents. Functional studies were not performed. In a Japanese patient (patient 3), born to nonconsanguineous parents, with NMIHBA, Imagawa et al. (2018) identified compound heterozygous mutations in the PRUNE1 gene: D106N and a c.540T-A transition in exon 5, resulting in a cys180-to-ter (C180X; 617413.0009) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were identified in the carrier state in the parents. Studies in lymphoblastoid cells from patient 3 demonstrated that the C180X mutation resulted in nonsense-mediated decay of the PRUNE1 mRNA. In 3 Lebanese sibs (family 1), born to consanguineous parents, with NMIHBA, Alhaddad et al. (2018) identified homozygosity for the D106N mutation in the PRUNE1 gene. The mutation, which was identified by a combination of parametric linkage analysis, whole-exome sequencing, and Sanger sequencing, segregated with the disorder in the family. In 4 Turkish patients, including 1 sib pair, from 3 families (families 2, 3 and 5) with NMIHBA, Alhaddad et al. (2018) identified homozygosity for the D106N mutation in the PRUNE1 gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in each family. (less)
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Comment:
Comment:
Observed as a homozygote.
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with PRUNE1-related neurodevelopmental conditions (PMID: 26539891, 28334956, 29797509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 402131). This variant is present in population databases (rs773618224, ExAC 0.02%). This sequence change replaces aspartic acid with asparagine at codon 106 of the PRUNE1 protein (p.Asp106Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine.
Comment:
The missense variant c.316G>A (p.Asp106Asn) in PRUNE1 gene has been reported to be homozygous in several individuals with syndromic intellectual disability (Karaca E et.al.,2015). Experimental studies show that missense change affect PRUNE1 function (Zollo M et.al .,2017). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Asp106Asn variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.00005177% is reported in gnomAD. The amino acid Asp at position 106 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. 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:
There are 3 more families with similar phenotype
Comment:
Observed as a homozygote.
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with PRUNE1-related neurodevelopmental conditions (PMID: 26539891, 28334956, 29797509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 402131). This variant is present in population databases (rs773618224, ExAC 0.02%). This sequence change replaces aspartic acid with asparagine at codon 106 of the PRUNE1 protein (p.Asp106Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine.
Comment:
The missense variant c.316G>A (p.Asp106Asn) in PRUNE1 gene has been reported to be homozygous in several individuals with syndromic intellectual disability (Karaca E et.al.,2015). Experimental studies show that missense change affect PRUNE1 function (Zollo M et.al .,2017). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Asp106Asn variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.00005177% is reported in gnomAD. The amino acid Asp at position 106 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum. | Alhaddad B | Neuropediatrics | 2018 | PMID: 29940663 |
| PRUNE1-related disorder: Expanding the clinical spectrum. | Imagawa E | Clinical genetics | 2018 | PMID: 29797509 |
| PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment. | Zollo M | Brain : a journal of neurology | 2017 | PMID: 28334956 |
| Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. | Karaca E | Neuron | 2015 | PMID: 26539891 |
Text-mined citations for rs773618224 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.