NM_003900.5(SQSTM1):c.286C>T (p.Arg96Ter) AND Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 20, 2024
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:: RCV000256198.3

Allele description [Variation Report for NM_003900.5(SQSTM1):c.286C>T (p.Arg96Ter)]

NM_003900.5(SQSTM1):c.286C>T (p.Arg96Ter)

Gene:

SQSTM1:sequestosome 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q35.3

Genomic location:

Preferred name:

NM_003900.5(SQSTM1):c.286C>T (p.Arg96Ter)

HGVS:

NC_000005.10:g.179823038C>T
NG_011342.1:g.21651C>T
NM_001142298.2:c.34C>T
NM_001142299.2:c.34C>T
NM_003900.5:c.286C>TMANE SELECT
NP_001135770.1:p.Arg12Ter
NP_001135771.1:p.Arg12Ter
NP_003891.1:p.Arg96Ter
NC_000005.9:g.179250038C>T
NM_003900.4:c.286C>T

Protein change:

R12*; ARG96TER

Links:

OMIM: 601530.0010; dbSNP: rs886039782

NCBI 1000 Genomes Browser:

rs886039782

Molecular consequence:

NM_001142298.2:c.34C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001142299.2:c.34C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003900.5:c.286C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (NADGP)
Identifiers:: MONDO: MONDO:0014940; MedGen: C4310693; OMIM: 617145

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leucine--tRNA ligase [Pseudoalteromonas sp. S2721]
leucine--tRNA ligase [Pseudoalteromonas sp. S2721]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322748	OMIM	no assertion criteria provided	Pathogenic (Oct 10, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003804938	Institute of Human Genetics, University Hospital Muenster	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 4, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004801680	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 20, 2024)	inherited	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

SCV000322748

OMIM

no assertion criteria provided

Pathogenic
(Oct 10, 2016)

germline

literature only

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

SCV003804938

Institute of Human Genetics, University Hospital Muenster

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 4, 2022)

unknown

clinical testing

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

SCV004801680

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 20, 2024)

inherited

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	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	inherited	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.

Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P, Maffezzini C, Lönnqvist T, Suomalainen A, Gorza M, Kremer LS, Graf E, Hartig M, Berutti R, Paucar M, Svenningsson P, Stranneheim H, Brandberg G, Wedell A, Kurian MA, Hayflick SA, Venco P, Tiranti V, et al.

Am J Hum Genet. 2016 Sep 1;99(3):735-743. doi: 10.1016/j.ajhg.2016.06.026. Epub 2016 Aug 18.

PubMed [citation]

PMID:: 27545679
PMCID:: PMC5010644

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, SCV000322748.1

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

Description

In 2 sibs, born of consanguineous Kurdish parents, with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP; 617145), Haack et al. (2016) identified a homozygous c.286C-T transition (c.286C-T, NM_003900.4) in exon 2 of the SQSTM1 gene, resulting in an arg96-to-ter (R96X) substitution. An unrelated girl of Finnish descent was also homozygous for this mutation; her parents were not related. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing in both families, was filtered against the ExAC database, and segregated with the disorder in the families. Biallelic loss of function SQSTM1 mutations were not found in 7,000 in-house exomes or in the ExAC database. Patient fibroblasts showed absence of the SQSTM1 protein.

#	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 Hospital Muenster, SCV003804938.1

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

Description

ACMG categories: PVS1,PS1,PP5

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

From Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SCV004801680.1

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

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

Last Updated: Sep 29, 2024

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