NM_001128126.3(AP4S1):c.124C>T (p.Arg42Ter) AND Spastic paraplegia 52, autosomal recessive

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 22, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000023635.6

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]

Observations:

Condition(s)

Name:: Spastic paraplegia 52, autosomal recessive (SPG52)
Synonyms:: Cerebral palsy, spastic quadriplegic, 6
Identifiers:: MONDO: MONDO:0013552; MedGen: C3279743; Orphanet: 280763; OMIM: 614067

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000044926	OMIM	no assertion criteria provided	Pathogenic (Jun 10, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001443020	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2020)	biparental	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002521439	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000044926

OMIM

no assertion criteria provided

Pathogenic
(Jun 10, 2011)

germline

literature only

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

SCV001443020

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 1, 2020)

biparental

clinical testing

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

SCV002521439

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 22, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000044926.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

By linkage analysis followed by exome sequencing of a consanguineous Syrian family with autosomal recessive mental retardation and spasticity (SPG52; 614067), Abou Jamra et al. (2011) identified a homozygous 124C-T transition in exon 2 of the AP4S1 gene, resulting in an arg42-to-ter (R42X) substitution. The mutation was not found in 740 control chromosomes of Syrian descent.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001443020.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2,PP1_Strong

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002521439.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense): 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: VCV000030658). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine