NM_002495.4(NDUFS4):c.221del (p.Thr74fs) AND Leigh syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 10, 2023
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:: RCV003155692.1

Allele description [Variation Report for NM_002495.4(NDUFS4):c.221del (p.Thr74fs)]

NM_002495.4(NDUFS4):c.221del (p.Thr74fs)

Gene:

NDUFS4:NADH:ubiquinone oxidoreductase subunit S4 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

5q11.2

Genomic location:

Preferred name:

NM_002495.4(NDUFS4):c.221del (p.Thr74fs)

HGVS:

NC_000005.10:g.53646276del
NG_008200.1:g.90642del
NM_001318051.2:c.221del
NM_002495.3:c.221delC
NM_002495.4:c.221delMANE SELECT
NP_001304980.1:p.Thr74fs
NP_002486.1:p.Thr74fs
NC_000005.9:g.52942106del
NM_002495.4:c.221del
NR_134473.2:n.417del
NR_134474.2:n.334del
NR_134475.2:n.369del

Protein change:

T74fs

Molecular consequence:

NM_001318051.2:c.221del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002495.4:c.221del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_134473.2:n.417del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134474.2:n.334del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134475.2:n.369del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Leigh syndrome (NULS)
Synonyms:: Leigh Disease; Subacute necrotizing encephalopathy; Necrotizing encephalopathy infantile subacute of Leigh; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009723; MedGen: C0023264; Orphanet: 506; OMIM: 256000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003844502	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20818383, 22326555 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003844502

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Feb 10, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency.

Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, Rivas M, Guiducci C, Bruno DL, Goldberger OA, Redman MC, Wiltshire E, Wilson CJ, Altshuler D, Gabriel SB, Daly MJ, Thorburn DR, Mootha VK.

Nat Genet. 2010 Oct;42(10):851-8. doi: 10.1038/ng.659. Epub 2010 Sep 5.

PubMed [citation]

PMID:: 20818383
PMCID:: PMC2977978

A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome.

Assouline Z, Jambou M, Rio M, Bole-Feysot C, de Lonlay P, Barnerias C, Desguerre I, Bonnemains C, Guillermet C, Steffann J, Munnich A, Bonnefont JP, Rötig A, Lebre AS.

Biochim Biophys Acta. 2012 Jun;1822(6):1062-9. doi: 10.1016/j.bbadis.2012.01.013. Epub 2012 Feb 3.

PubMed [citation]

PMID:: 22326555

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844502.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: NDUFS4 c.221delC (p.Thr74IlefsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250788 control chromosomes (gnomAD). c.221delC has been reported in the literature in at least one homozygous individual with a confirmed mitochondrial complex I deficiency (Calvo_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: May 19, 2024

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