Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 34402213, 25496299, 24700674, 25558065, 32979048, 28464862)
ClinVar Genomic variation as it relates to human health
NM_004722.4(AP4M1):c.1012C>T (p.Arg338Ter)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004722.4(AP4M1):c.1012C>T (p.Arg338Ter)
Variation ID: 209980 Accession: VCV000209980.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q22.1 7: 100106278 (GRCh38) [ NCBI UCSC ] 7: 99703901 (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 Sep 29, 2015 Feb 20, 2024 Dec 2, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004722.4:c.1012C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004713.2:p.Arg338Ter nonsense NM_001363671.2:c.1033C>T NP_001350600.1:p.Arg345Ter nonsense NC_000007.14:g.100106278C>T NC_000007.13:g.99703901C>T NG_016312.1:g.9772C>T NG_029454.1:g.18581G>A - Protein change
- R338*, R345*
- Other names
- -
- Canonical SPDI
- NC_000007.14:100106277: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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loss_of_function_variant; Sequence Ontology [ SO:0002054]
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- 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. |
|||
| AP4M1 | - | - |
GRCh38 GRCh37 |
407 | 495 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 5, 2022 | RCV000191922.13 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Oct 1, 2020 | RCV001849336.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 2, 2022 | RCV003227707.1 |
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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Pathogenic
(Dec 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003924753.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 34402213, 25496299, 24700674, 25558065, 32979048, 28464862) (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 50
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV004013549.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000209980 / PMID: 24700674). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Microangiopathic hemolytic anemia (present) , Global developmental delay (present)
|
|
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Pathogenic
(Oct 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 50
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002236504.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 209980). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal … (more)
ClinVar contains an entry for this variant (Variation ID: 209980). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with spastic paraplegia (PMID: 24700674, 28464862). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs146262009, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg338*) in the AP4M1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4M1 are known to be pathogenic (PMID: 24700674, 25496299, 25558065). (less)
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Pathogenic
(Jul 01, 2014)
|
no assertion criteria provided
Method: literature only
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SPASTIC PARAPLEGIA 50, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000246145.2
First in ClinVar: Sep 29, 2015 Last updated: Aug 03, 2021 |
Comment on evidence:
In 2 sisters (family 1), born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-50 (SPG50; 612936), Tuysuz et al. (2014) identified a homozygous c.1012C-T … (more)
In 2 sisters (family 1), born of consanguineous Turkish parents, with autosomal recessive spastic paraplegia-50 (SPG50; 612936), Tuysuz et al. (2014) identified a homozygous c.1012C-T transition (chr7.99,541,837C-T, NCBI36) in exon 13 of the AP4M1 gene, resulting in an arg338-to-ter (R338X) substitution. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. The mutation occurred in the mu homology domain and was not found in the dbSNP (build 131) or 1000 Genomes Project databases, or in control chromosomes. Functional studies of the variant and studies of patient cells were not performed. (less)
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Likely pathogenic
(Jan 01, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary spastic paraplegia 50
Affected status: yes
Allele origin:
inherited
|
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles
Accession: SCV001481940.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
|
|
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Likely pathogenic
(Oct 01, 2020)
|
no assertion criteria provided
Method: literature only
|
Spastic paraplegia
Affected status: yes
Allele origin:
germline
|
Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106860.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary spastic paraplegia 50
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Clinical Genetics Laboratory, CHRU Nancy
Accession: SCV002547281.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Clinical Features:
Spasticity (present) , Hypotonia (present) , Microcephaly (present) , Seizure (present) , Global developmental delay (present) , Absent speech (present) , Intellectual disability, severe (present) … (more)
Spasticity (present) , Hypotonia (present) , Microcephaly (present) , Seizure (present) , Global developmental delay (present) , Absent speech (present) , Intellectual disability, severe (present) , Oculomotor apraxia (present) , Strabismus (present) , Limb dystonia (present) , Cerebral cortical atrophy (present) , Hypoplasia of the corpus callosum (present) , Delayed CNS myelination (present) , Hippocampal sclerosis (present) , Pineal gland calcification (present) (less)
Sex: female
Ethnicity/Population group: Turkish
|
Comment:
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000209980 / PMID: 24700674). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
ClinVar contains an entry for this variant (Variation ID: 209980). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with spastic paraplegia (PMID: 24700674, 28464862). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs146262009, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg338*) in the AP4M1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4M1 are known to be pathogenic (PMID: 24700674, 25496299, 25558065).
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
loss_of_function_variant
|
Clinical Genetics Laboratory, CHRU Nancy
Accession: SCV002547281.1
|
|
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 34402213, 25496299, 24700674, 25558065, 32979048, 28464862)
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000209980 / PMID: 24700674). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
ClinVar contains an entry for this variant (Variation ID: 209980). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with spastic paraplegia (PMID: 24700674, 28464862). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs146262009, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Arg338*) in the AP4M1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4M1 are known to be pathogenic (PMID: 24700674, 25496299, 25558065).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families. | Becker A | Clinical genetics | 2023 | PMID: 36371792 |
| Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. | Ebrahimi-Fakhari D | Brain : a journal of neurology | 2020 | PMID: 32979048 |
| Severe congenital microcephaly with AP4M1 mutation, a case report. | Duerinckx S | BMC medical genetics | 2017 | PMID: 28464862 |
| Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. | Alazami AM | Cell reports | 2015 | PMID: 25558065 |
| A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency. | Jameel M | BMC medical genetics | 2014 | PMID: 25496299 |
| Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. | Tüysüz B | American journal of medical genetics. Part A | 2014 | PMID: 24700674 |
Text-mined citations for rs146262009 ...
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 Sep 29, 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.