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NM_001128126.3(AP4S1):c.124C>T (p.Arg42Ter) AND Spastic paraplegia

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Dec 31, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001849280.3

Allele description [Variation Report for NM_001128126.3(AP4S1):c.124C>T (p.Arg42Ter)]

NM_001128126.3(AP4S1):c.124C>T (p.Arg42Ter)

Gene:
AP4S1:adaptor related protein complex 4 subunit sigma 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q12
Genomic location:
Preferred name:
NM_001128126.3(AP4S1):c.124C>T (p.Arg42Ter)
HGVS:
  • NC_000014.9:g.31066320C>T
  • NG_031913.1:g.46215C>T
  • NM_001128126.3:c.124C>TMANE SELECT
  • NM_001254726.2:c.124C>T
  • NM_001254727.2:c.124C>T
  • NM_001254728.2:c.124C>T
  • NM_001254729.2:c.124C>T
  • NM_007077.5:c.124C>T
  • NP_001121598.1:p.Arg42Ter
  • NP_001241655.1:p.Arg42Ter
  • NP_001241656.1:p.Arg42Ter
  • NP_001241657.1:p.Arg42Ter
  • NP_001241658.1:p.Arg42Ter
  • NP_009008.2:p.Arg42Ter
  • NP_009008.2:p.Arg42Ter
  • NC_000014.8:g.31535526C>T
  • NM_007077.4:c.124C>T
  • p.Arg42*
Protein change:
R42*; ARG42TER
Links:
OMIM: 607243.0001; dbSNP: rs387906970
NCBI 1000 Genomes Browser:
rs387906970
Molecular consequence:
  • NM_001128126.3:c.124C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001254726.2:c.124C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001254727.2:c.124C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001254728.2:c.124C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001254729.2:c.124C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_007077.5:c.124C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Spastic paraplegia
Identifiers:
MedGen: C0037772; Human Phenotype Ontology: HP:0001258

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002106896Yale Center for Mendelian Genomics, Yale University - Yale Center for Mendelian Genomics
no assertion criteria provided
Likely pathogenic
(Oct 1, 2020) 		germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV004286332Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 31, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes2not providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kölker S, Volkmann J, et al.

Brain. 2020 Oct 1;143(10):2929-2944. doi: 10.1093/brain/awz307. Erratum in: Brain. 2021 Apr 12;144(3):e33. doi: 10.1093/brain/awaa424.

PubMed [citation]
PMID:
32979048
PMCID:
PMC7780481

Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.

Abou Jamra R, Philippe O, Raas-Rothschild A, Eck SH, Graf E, Buchert R, Borck G, Ekici A, Brockschmidt FF, Nöthen MM, Munnich A, Strom TM, Reis A, Colleaux L.

Am J Hum Genet. 2011 Jun 10;88(6):788-795. doi: 10.1016/j.ajhg.2011.04.019. Epub 2011 May 27.

PubMed [citation]
PMID:
21620353
PMCID:
PMC3113253
See all PubMed Citations (5)

Details of each submission

From Yale Center for Mendelian Genomics, Yale University - Yale Center for Mendelian Genomics, SCV002106896.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004286332.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 30658). This premature translational stop signal has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 21620353, 32979048; Invitae). This variant is present in population databases (rs387906970, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg42*) 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024