VCV000234924.37 - ClinVar

NM_001128126.3(AP4S1):c.289C>T (p.Arg97Ter)

Germline

Classification

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.

(19)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001128126.3(AP4S1):c.289C>T (p.Arg97Ter)

Variation ID: 234924 Accession: VCV000234924.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q12 14: 31072968 (GRCh38) [ NCBI UCSC ] 14: 31542174 (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	May 29, 2016	Jul 15, 2024	May 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001128126.3:c.289C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121598.1:p.Arg97Ter	nonsense
NM_001254726.2:c.289C>T	NP_001241655.1:p.Arg97Ter	nonsense
NM_001254727.2:c.289C>T	NP_001241656.1:p.Arg97Ter	nonsense
NM_001254728.2:c.289C>T	NP_001241657.1:p.Arg97Ter	nonsense
NM_001254729.2:c.289C>T	NP_001241658.1:p.Arg97Ter	nonsense
NM_007077.5:c.289C>T	NP_009008.2:p.Arg97Ter	nonsense
NC_000014.9:g.31072968C>T
NC_000014.8:g.31542174C>T
NG_031913.1:g.52863C>T

... more HGVS ... less HGVS

Protein change

R97*

Other names

Canonical SPDI

NC_000014.9:31072967:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00009

Trans-Omics for Precision Medicine (TOPMed) 0.00011

Exome Aggregation Consortium (ExAC) 0.00012

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Links

ClinGen: CA7144219 OMIM: 607243.0003 dbSNP: rs200440467 VarSome

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
Gene	OMIM	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.
AP4S1		-	-	GRCh38 GRCh37	134	168

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.
Spastic paraplegia 52, autosomal recessive	Pathogenic/Likely pathogenic (11)	criteria provided, multiple submitters, no conflicts	May 22, 2024	RCV000223666.32
Spastic paraplegia	Pathogenic (2)	criteria provided, single submitter	Aug 5, 2023	RCV000525844.14
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 24, 2023	RCV000443008.18
Intellectual disability	Pathogenic (1)	criteria provided, single submitter	Sep 10, 2020	RCV001260893.9
AP4S1-related disorder	not provided (1)	no classification provided	-	RCV001249232.9

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.
Likely pathogenic (Jan 06, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spastic paraplegia 52, autosomal recessive Affected status: yes Allele origin: inherited	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris Accession: SCV000586778.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016	Publications: PubMed (1) PubMed: 28708303 Comment: Intellectual disability, moderate; acquired microcephaly (-4SD); hypotonia; epilepsy (starting at 2 months old) Number of individuals with the variant: 1 Age: 0-9 years Sex: female
Pathogenic (Feb 16, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000859814.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AP4S1 Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Jan 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000593255.2 First in ClinVar: Aug 28, 2017 Last updated: Jan 29, 2022
Pathogenic (Mar 24, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000521309.5 First in ClinVar: Mar 08, 2017 Last updated: Apr 15, 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 disease; This … (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: 25552650, 29302074, 31130284, 32371413, 33644862, 32895917, 32979048, 31345219, 27535533, 28708303) (less)
Pathogenic (Aug 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Spastic paraplegia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000629434.4 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 25552650‚ 21620353‚ 27444738 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 234924). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 234924). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 25552650). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs200440467, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg97*) in the AP4S1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4S1 are known to be pathogenic (PMID: 21620353, 25552650, 27444738). (less)
Pathogenic (Feb 22, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spastic paraplegia 52, autosomal recessive Affected status: yes Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV001423591.1 First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020	Comment: [ACMG/AMP: PVS1, PM2, PM3, PP1] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is absent … (more) [ACMG/AMP: PVS1, PM2, PM3, PP1] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], has been shown to cosegregate with disease in multiple affected family members [PP1]. (less)
Pathogenic (Sep 10, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability Affected status: yes Allele origin: unknown	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001437993.1 First in ClinVar: Oct 20, 2020 Last updated: Oct 20, 2020
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447536.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Global developmental delay (present) , Intellectual disability (present) , Hypotonia (present) , Spasticity (present) Sex: male
Pathogenic (Apr 02, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spastic paraplegia 52, autosomal recessive Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368406.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Pathogenic (Dec 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spastic paraplegia 52, autosomal recessive (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV001478364.1 First in ClinVar: Feb 07, 2021 Last updated: Feb 07, 2021	Number of individuals with the variant: 3 Family history: yes Sex: male
Pathogenic (Feb 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spastic paraplegia 52, autosomal recessive Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002792570.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Nov 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spastic paraplegia 52, autosomal recessive (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004175975.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Comment: Criteria applied: PVS1,PS4_MOD,PM3,PM2_SUP Clinical Features: Focal impaired awareness seizure (present) , Status epilepticus (present) , Cerebral visual impairment (present) , Nystagmus (present) , Microcephaly (present) , Bilateral tonic-clonic seizure with … (more) Focal impaired awareness seizure (present) , Status epilepticus (present) , Cerebral visual impairment (present) , Nystagmus (present) , Microcephaly (present) , Bilateral tonic-clonic seizure with focal onset (present) , Intellectual disability, severe (present) , Spastic tetraparesis (present) , Dysphagia (present) (less) Sex: male
Pathogenic (Jul 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spastic paraplegia 52, autosomal recessive Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021412.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spastic paraplegia 52, autosomal recessive Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806903.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (May 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spastic paraplegia 52, autosomal recessive Affected status: yes Allele origin: biparental	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005077715.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Comment: ACMG Criteria: PVS1, PS3, PM3, PM2_P, PP5; Variant was found in homozygous state in both the patient and the patient's brother (also affected). Clinical Features: Global developmental delay (present) , Absent speech (present) , Motor delay (present) , Seizure (present) , Microcephaly (present) , Failure to thrive (present) , Strabismus … (more) Global developmental delay (present) , Absent speech (present) , Motor delay (present) , Seizure (present) , Microcephaly (present) , Failure to thrive (present) , Strabismus (present) , Bruxism (present) , Psoriasiform lesion (present) , Tented upper lip vermilion (present) (less)
Pathogenic (Jun 21, 2018)	no assertion criteria provided Method: literature only	SPASTIC PARAPLEGIA 52, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000280013.2 First in ClinVar: May 29, 2016 Last updated: Jun 25, 2018	Publications: PubMed (1) PubMed: 25552650 Comment on evidence: For discussion of the c.289C-T transition (c.289C-T, NM_007077.4) in the AP4S1 gene resulting in an arg97-to-ter (R97X) substitution that was found in compound heterozygous state … (more) For discussion of the c.289C-T transition (c.289C-T, NM_007077.4) in the AP4S1 gene resulting in an arg97-to-ter (R97X) substitution that was found in compound heterozygous state in patients with autosomal recessive spastic paraplegia-52 (SPG52; 614067) by Hardies et al. (2015), see 607243.0002. (less)
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: SCV002106897.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (1) PubMed: 32979048
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Spastic paraplegia 52, autosomal recessive Affected status: yes Allele origin: germline	Dr.Nikuei Genetic Center Accession: SCV005061407.1 First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024
not provided (-)	no classification provided Method: phenotyping only	AP4S1-related disorder Affected status: yes Allele origin: maternal	GenomeConnect, ClinGen Accession: SCV001423167.1 First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020	Comment: Variant interpretted as Pathogenic and reported on 04-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpretted as Pathogenic and reported on 04-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Abnormal delivery (present) , Short stature (present) , Abnormality of the skull (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , … (more) Abnormal delivery (present) , Short stature (present) , Abnormality of the skull (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Hypertonia (present) , Generalized hypotonia (present) , Memory impairment (present) , Seizures (present) , Abnormality of the curvature of the vertebral column (present) , Joint hypermobility (present) , Hip dysplasia (present) , Abnormality of facial musculature (present) , Abnormality of muscle physiology (present) , Abnormality of esophagus morphology (present) , Gingivitis (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Testing laboratory: GeneDx Date variant was reported to submitter: 2018-04-16 Testing laboratory interpretation: Pathogenic
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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: 25552650, 29302074, 31130284, 32371413, 33644862, 32895917, 32979048, 31345219, 27535533, 28708303)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 234924). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 25552650). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs200440467, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg97*) in the AP4S1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4S1 are known to be pathogenic (PMID: 21620353, 25552650, 27444738).

Comment:

[ACMG/AMP: PVS1, PM2, PM3, PP1] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], has been shown to cosegregate with disease in multiple affected family members [PP1].

Comment:

Variant interpretted as Pathogenic and reported on 04-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families.	Tessa A	European journal of neurology	2016	PMID: 27444738
Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly.	Hardies K	Human molecular genetics	2015	PMID: 25552650
Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.	Abou Jamra R	American journal of human genetics	2011	PMID: 21620353
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AP4S1	-	-	-	-

Text-mined citations for rs200440467 ...

These 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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001128126.3(AP4S1):c.289C>T (p.Arg97Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200440467 ...