ClinVar Genomic variation as it relates to human health
NM_007118.4(TRIO):c.3232C>T (p.Arg1078Trp)
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.
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(6); Likely pathogenic(5); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007118.4(TRIO):c.3232C>T (p.Arg1078Trp)
Variation ID: 449111 Accession: VCV000449111.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p15.2 5: 14374244 (GRCh38) [ NCBI UCSC ] 5: 14374353 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 19, 2017 Feb 28, 2024 Dec 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007118.4:c.3232C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009049.2:p.Arg1078Trp missense NR_134469.2:n.3616C>T non-coding transcript variant NC_000005.10:g.14374244C>T NC_000005.9:g.14374353C>T NG_052962.1:g.235543C>T - Protein change
- R1078W
- Other names
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- Canonical SPDI
- NC_000005.10:14374243:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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TRIO | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1173 | 1347 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000522592.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 14, 2016 | RCV000623993.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 3, 2017 | RCV000760240.2 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2022 | RCV000995906.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV001030433.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 10, 2020 | RCV001260804.2 |
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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Likely pathogenic
(Nov 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 28
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV000890073.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
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Likely pathogenic
(Jun 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München
Accession: SCV001150299.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Sep 10, 2020)
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criteria provided, single submitter
Method: curation
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Intellectual developmental disorder, autosomal dominant 63, with macrocephaly
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV001432993.1
First in ClinVar: Sep 24, 2020 Last updated: Sep 24, 2020 |
Comment:
This variant is interpreted as pathogenic for Intellectual developmental disorder, autosomal dominant 63, with macrocephaly. The following ACMG Tag(s) were applied: Absent from controls (or … (more)
This variant is interpreted as pathogenic for Intellectual developmental disorder, autosomal dominant 63, with macrocephaly. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2 upgraded to very strong); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1); Well-established functional studies show a deleterious effect (PS3 downgraded to moderate). (less)
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Uncertain significance
(Sep 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
de novo
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Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV001437897.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Method: targeted next-gen sequencing
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV001468929.1
First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
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Pathogenic
(Sep 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934542.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Comment:
This variant was identified as de novo (maternity and paternity confirmed).
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual developmental disorder, autosomal dominant 63, with macrocephaly
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058704.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been previously reported as de novo in a similarly affected individual (PMID: 32109419, PS2_S). Functional studies provide strong evidence of the variant … (more)
The variant has been previously reported as de novo in a similarly affected individual (PMID: 32109419, PS2_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32109419, , PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000830226, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.94, PP3_P). 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:
Midface retrusion (present) , Frontal bossing (present) , Global developmental delay (present) , Generalized hypotonia (present) , Joint laxity (present) , Short finger (present) , … (more)
Midface retrusion (present) , Frontal bossing (present) , Global developmental delay (present) , Generalized hypotonia (present) , Joint laxity (present) , Short finger (present) , Short nose (present) , Short humerus (present) , Cryptorchidism (present) (less)
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Likely pathogenic
(Oct 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741633.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Asian/Japanese/Chinese
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Hispanic/Dominican
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Pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000616903.5
First in ClinVar: Dec 19, 2017 Last updated: Nov 11, 2023 |
Comment:
Published functional studies demonstrate a damaging effect by altering overall protein folding and/or signaling (Barbosa et al., 2020); Not observed at significant frequency in large … (more)
Published functional studies demonstrate a damaging effect by altering overall protein folding and/or signaling (Barbosa et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33619735, 32109419, 33568469, 31130284, 35174982) (less)
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Pathogenic
(Dec 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
Affected status: yes
Allele origin:
de novo
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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV003803924.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Sex: female
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Likely pathogenic
(Dec 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003806888.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM6 moderated, PP2 supporting
Number of individuals with the variant: 1
Clinical Features:
Secondary Caesarian section (present) , Abnormal delivery (present) , Caesarian section (present) , Delayed ability to walk (present) , Delayed gross motor development (present) , … (more)
Secondary Caesarian section (present) , Abnormal delivery (present) , Caesarian section (present) , Delayed ability to walk (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Moderate global developmental delay (present) , Generalized hypotonia (present) , Global developmental delay (present) , Delayed ability to stand (present) , Seizure (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002247367.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1078 of the TRIO protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1078 of the TRIO protein (p.Arg1078Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a neurodevelopmental disorder (PMID: 32109419). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449111). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRIO protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TRIO function (PMID: 32109419). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 31, 2020)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 63, WITH MACROCEPHALY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001193441.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
Comment on evidence:
In 4 unrelated boys (patients 2-5) with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; 618825), Barbosa et al. (2020) identified a de novo heterozygous … (more)
In 4 unrelated boys (patients 2-5) with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; 618825), Barbosa et al. (2020) identified a de novo heterozygous c.3232C-T transition (c.3232C-T, NM_007118) in the TRIO gene, resulting in an arg1078-to-trp (R1078W) substitution at a highly conserved residue in the seventh spectrin repeat domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Molecular modeling predicted that the mutation could cause steric hindrance and alter the structural organization of the protein or protein folding. Expression of the mutation into HEK293 cells resulted in increased RAC1 (602048) activation, as measured by increased PAK1 (602590) phosphorylation, compared to wildtype. Transfection of the mutation into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956925.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963194.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders. | Barbosa S | American journal of human genetics | 2020 | PMID: 32109419 |
Text-mined citations for this variant ...
HelpRecord last updated Mar 05, 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.