ClinVar Genomic variation as it relates to human health
NM_145207.3(AFG2A):c.983CAA[2] (p.Thr330del)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_145207.3(AFG2A):c.983CAA[2] (p.Thr330del)
Variation ID: 207828 Accession: VCV000207828.44
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 4q28.1 4: 122934574-122934576 (GRCh38) [ NCBI UCSC ] 4: 123855729-123855731 (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 Aug 7, 2015 Apr 15, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_145207.3:c.983CAA[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_660208.2:p.Thr330del inframe deletion NM_145207.3:c.989_991del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001317799.2:c.980CAA[2] NP_001304728.1:p.Thr329del inframe deletion NM_001345856.2:c.980CAA[2] NP_001332785.1:p.Thr329del inframe deletion NM_145207.2:c.989_991del NC_000004.12:g.122934574CAA[2] NC_000004.11:g.123855729CAA[2] NG_051570.1:g.16505CAA[2] - Protein change
- T330del, T329del
- Other names
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- Canonical SPDI
- NC_000004.12:122934573:CAACAACAA:CAACAA
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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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AFG2A | - | - |
GRCh38 GRCh37 |
756 | 783 |
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 (9) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2023 | RCV000190122.30 | |
Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000578291.17 |
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
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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
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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
(May 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000609648.1
First in ClinVar: Aug 07, 2015 Last updated: Aug 07, 2015 |
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Likely pathogenic
(Sep 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680392.1
First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018 |
Sex: male
Tissue: blood
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Likely pathogenic
(Apr 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000837695.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Number of individuals with the variant: 1
Clinical Features:
Widely spaced teeth (present) , Ulnar deviation of the wrist (present) , Thin vermilion border (present) , Thick hair (present) , Temperature instability (present) , … (more)
Widely spaced teeth (present) , Ulnar deviation of the wrist (present) , Thin vermilion border (present) , Thick hair (present) , Temperature instability (present) , Tapered finger (present) , Stereotypy (present) , Stereotypical hand wringing (present) , Spasticity (present) , Sleep disturbance (present) , Short neck (present) , Seizures (present) , Reduced tendon reflexes (present) , Recurrent infections (present) , Open mouth (present) , Narrow chest (present) , Minimal subcutaneous fat (present) , Microcephaly (present) , Medial flaring of the eyebrow (present) , Low anterior hairline (present) , Long face (present) , Labial hypoplasia (present) , Infantile spasms (present) , Induced vaginal delivery (present) , IgG deficiency (present) , IgA deficiency (present) , Hypopigmentation of the fundus (present) , Hyperactive patellar reflex (present) , Hip dysplasia (present) , Highly arched eyebrow (present) , High palate (present) , Hand clenching (present) , Global developmental delay (present) , Generalized hypotonia (present) , Gastroparesis (present) , Gastrointestinal dysmotility (present) , Frontal upsweep of hair (present) , Failure to thrive (present) , EEG abnormality (present) , Dyskinesia (present) , Developmental regression (present) , Depressed nasal bridge (present) , Decreased fetal movement (present) , Cortical visual impairment (present) , Congenital sensorineural hearing impairment (present) , Cerebral atrophy (present) , Broad proximal phalanx of the hallux (present) , Brachycephaly (present) , Astigmatism (present) , Almond-shaped palpebral fissure (present) , Abnormality of mitochondrial metabolism (present) , Abnormal delivery (present) , 2-3 toe syndactyly (present) (less)
Age: 10-19 years
Sex: female
Ethnicity/Population group: White
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2018-02-05
Testing laboratory interpretation: Uncertain significance
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Likely pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448089.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hearing impairment (present) , Global developmental delay (present) , Spastic tetraparesis (present) , Short stature (present) , Microcephaly (present)
Sex: female
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Likely pathogenic
(Jun 26, 2017)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002064336.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely pathogenic
(Feb 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001439959.2
First in ClinVar: Oct 30, 2020 Last updated: Mar 05, 2022 |
Comment:
This variant was identified as compound heterozygous with NM_145207.3:c.2166_2176del._x000D_ Criteria applied: PM3_VSTR, PM4
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
Affected status: yes
Allele origin:
inherited
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559184.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
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Likely pathogenic
(Mar 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581290.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766863.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (MIM#616577). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 29 heterozygotes, 1 homozygote). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (p.(Thr330Ala) - v2: 1 heterozygote, 0 homozygotes; p.(Thr330Arg) - v3: 1 heterozygote, 0 homozygotes). (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many affected individuals (PMIDs: 29343804, 34360601) and as pathogenic/likely pathogenic many times in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000825226.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This variant, c.989_991del, results in the deletion of 1 amino acid(s) of the SPATA5 protein (p.Thr330del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.989_991del, results in the deletion of 1 amino acid(s) of the SPATA5 protein (p.Thr330del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs748291365, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with epilepsy, hearing loss, and intellectual disability syndrome (PMID: 26299366, 27246907, 27683084, 28293831). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 207828). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 16, 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: SCV000710049.6
First in ClinVar: Apr 02, 2018 Last updated: Mar 11, 2023 |
Comment:
In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with … (more)
In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26299366, 28293831, 27246907, 27683084, 29343804, 21822266, 30577886, 30552426, 30009132, 34426522, 33176815, 34360601, 31440721, 33177673) (less)
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Likely pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004808071.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jun 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247393.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 4
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Likely pathogenic
(Aug 03, 2015)
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Accession: SCV000240215.1
First in ClinVar: Aug 07, 2015 Last updated: Aug 07, 2015 |
Comment:
The p.T330del variant in the SPATA5 gene was found in the homozygous state and has not been reported previously as a disease-causing mutation nor as … (more)
The p.T330del variant in the SPATA5 gene was found in the homozygous state and has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The p.T330del variant results in the deletion of a single Threonine residue, denoted p.Thr330del, at a position that is conserved across species. The p.T330del variant was observed at an allele frequency of 0.0002 in approximately 33.000 individuals of European ancestry (ExAC database), indicating it is not a common benign variant in this population. However, in this database the variant is also present once in the homozygous state. Based on these data and because of highly similar clinical features between this patient and others with SPATA5 mutations we interpret the p.T330del variant as likely pathogenic. (less)
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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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809797.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932168.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965227.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Feb 11, 2022)
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no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER WITH HEARING LOSS, SEIZURES, AND BRAIN ABNORMALITIES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002097232.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment on evidence:
In 2 sibs with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577), Kurata et al. (2016) identified compound heterozygous mutations in the … (more)
In 2 sibs with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577), Kurata et al. (2016) identified compound heterozygous mutations in the SPATA5 gene: a 3-bp deletion (c.989_991del, NM_145207.2), resulting in an in-frame deletion of thr330 (Thr330del), inherited from the mother, and a 4-bp deletion (c.2130_2133del; 613940.0007), resulting in a frameshift and premature termination (Glu711ProfsTer21), inherited from the father. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. No functional studies were performed. (less)
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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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Muscular and Molecular Pathology Associated with SPATA5 Deficiency in a Child with EHLMRS. | Braun F | International journal of molecular sciences | 2021 | PMID: 34360601 |
Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency. | Puusepp S | European journal of human genetics : EJHG | 2018 | PMID: 29343804 |
Isolated Hearing Impairment Caused by SPATA5 Mutations in a Family with Variable Phenotypic Expression. | Szczałuba K | Advances in experimental medicine and biology | 2017 | PMID: 28293831 |
SPATA5 mutations cause a distinct autosomal recessive phenotype of intellectual disability, hypotonia and hearing loss. | Buchert R | Orphanet journal of rare diseases | 2016 | PMID: 27683084 |
Characterization of SPATA5-related encephalopathy in early childhood. | Kurata H | Clinical genetics | 2016 | PMID: 27246907 |
Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss. | Tanaka AJ | American journal of human genetics | 2015 | PMID: 26299366 |
Text-mined citations for rs796052243 ...
HelpRecord last updated Apr 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.