NM_002495.3(NDUFS4):c.462delA (p.Lys154Asnfs) AND Mitochondrial complex I deficiency, nuclear type 1

Clinical significance:Pathogenic (Last evaluated: Jul 1, 2014)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000133549.3

Allele description [Variation Report for NM_002495.3(NDUFS4):c.462delA (p.Lys154Asnfs)]

NM_002495.3(NDUFS4):c.462delA (p.Lys154Asnfs)

Gene:
NDUFS4:NADH:ubiquinone oxidoreductase subunit S4 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
5q11.2
Genomic location:
Preferred name:
NM_002495.3(NDUFS4):c.462delA (p.Lys154Asnfs)
HGVS:
  • NC_000005.10:g.53683155delA
  • NM_001318051.1:c.*25del
  • NM_002495.3:c.462del
  • NP_002486.1:p.Lys154Asnfs
  • NC_000005.9:g.52978985delA
  • NM_002495.2:c.462delA
  • p.K154NfsX35
Note:
NCBI staff reviewed the sequence information reported in PubMed 19107570 Fig. 1 to determine the location of this allele on the current reference sequence.
Links:
OMIM: 602694.0006; dbSNP: rs587776949
NCBI 1000 Genomes Browser:
rs587776949
Molecular consequence:
  • NM_002495.2:c.462delA - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Mitochondrial complex I deficiency, nuclear type 1 (MC1DN1)
Synonyms:
NADH-COENZYME Q REDUCTASE DEFICIENCY; MITOCHONDRIAL NADH DEHYDROGENASE COMPONENT OF COMPLEX I, DEFICIENCY OF
Identifiers:
MedGen: CN257533; OMIM: 252010

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000057114OMIMno assertion criteria providedPathogenic
(Jul 1, 2014)
germlineliterature only

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family.

Anderson SL, Chung WK, Frezzo J, Papp JC, Ekstein J, DiMauro S, Rubin BY.

J Inherit Metab Dis. 2008 Dec;31 Suppl 2:S461-7. doi: 10.1007/s10545-008-1049-9. Epub 2008 Dec 26.

PubMed [citation]
PMID:
19107570

Functional characterization of the c.462delA mutation in the NDUFS4 subunit gene of mitochondrial complex I.

Assereto S, Robbiano A, Di Rocco M, Rossi A, Cassandrini D, Panicucci C, Brigati G, Biancheri R, Bruno C, Minetti C, Trucks H, Sander T, Zara F, Gazzerro E.

Clin Genet. 2014 Jul;86(1):99-101. doi: 10.1111/cge.12248. Epub 2013 Sep 11. No abstract available.

PubMed [citation]
PMID:
24020637

Details of each submission

From OMIM, SCV000057114.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In 3 sibs, born of Ashkenazi Jewish parents, with complex I deficiency nuclear type 1 (MC1DN1; 252010) manifesting as Leigh syndrome (see 256000), Anderson et al. (2008) identified a homozygous 1-bp deletion (462delA) in the NDUFS4 gene, resulting in a shift in the reading frame and replacement of the last 22 amino acids with 34 novel amino acids. The mutation resulted in the loss of the cAMP-dependent protein kinase phosphorylation consensus site, which is important for activation of complex I. The mutation was identified by linkage analysis followed by candidate gene sequencing. Each unaffected parent and an unaffected sib were heterozygous for the mutation. The carrier frequency of the mutation, ascertained from 5,000 controls of Ashkenazi Jewish descent, was found to be 1 in 1,000, consistent with a founder effect in this population. Based on the results, Anderson et al. (2008) used prenatal testing in this family to help the parents produce an unaffected child.

Assereto et al. (2014) identified a homozygous 462delA mutation in 2 sibs with MC1DN1. Patient cells showed a 60% reduction in NDUFS4 transcript levels due to nonsense-mediated mRNA decay. No NDUFS4 or NDUFS6 (603848) proteins were detected in isolated mitochondria, consistent with inefficient assembly of complex I. Brain MRI did not show basal ganglia abnormalities, but there were abnormal T2-weighted hyperintensities involving the subthalamic nucleus and brainstem. Assereto et al. (2014) noted that the patients were not of Ashkenazi Jewish descent.

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

Last Updated: Apr 21, 2019

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