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NM_174889.5(NDUFAF2):c.13C>T (p.Gln5Ter) AND Mitochondrial complex 1 deficiency, nuclear type 10

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 9, 2024
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:
RCV004788106.1

Allele description [Variation Report for NM_174889.5(NDUFAF2):c.13C>T (p.Gln5Ter)]

NM_174889.5(NDUFAF2):c.13C>T (p.Gln5Ter)

Genes:
ERCC8:ERCC excision repair 8, CSA ubiquitin ligase complex subunit [Gene - OMIM - HGNC]
NDUFAF2:NADH:ubiquinone oxidoreductase complex assembly factor 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q12.1
Genomic location:
Preferred name:
NM_174889.5(NDUFAF2):c.13C>T (p.Gln5Ter)
HGVS:
  • NC_000005.10:g.60945268C>T
  • NG_008978.1:g.5140C>T
  • NG_009289.1:g.4811G>A
  • NM_174889.5:c.13C>TMANE SELECT
  • NP_777549.1:p.Gln5Ter
  • LRG_466t1:c.-260G>A
  • LRG_466:g.4811G>A
  • NC_000005.9:g.60241095C>T
  • NM_000082.3:c.-260G>A
  • NM_174889.4:c.13C>T
Protein change:
Q5*
Links:
dbSNP: rs772489808
NCBI 1000 Genomes Browser:
rs772489808
Molecular consequence:
  • NM_174889.5:c.13C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Mitochondrial complex 1 deficiency, nuclear type 10
Synonyms:
MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 10
Identifiers:
MONDO: MONDO:0032616; MedGen: C4748768; OMIM: 618233

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005399822Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Oct 9, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Leigh disease with brainstem involvement in complex I deficiency due to assembly factor NDUFAF2 defect.

Herzer M, Koch J, Prokisch H, Rodenburg R, Rauscher C, Radauer W, Forstner R, Pilz P, Rolinski B, Freisinger P, Mayr JA, Sperl W.

Neuropediatrics. 2010 Feb;41(1):30-4. doi: 10.1055/s-0030-1255062. Epub 2010 Jun 22.

PubMed [citation]
PMID:
20571988

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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005399822.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex I deficiency, nuclear type 10 (MIM#618233). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0703 - Other protein truncating variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. A downstream protein truncating variant located within the 5' NMD-escape region, p.(Gln27*), has been classified as likely pathogenic by a clinical laboratory in ClinVar. Additionally, p.(Trp3*), which is also located in the 5' NMD-escape region, has been reported in a homozygous individual with Leigh disease with brainstem involvement in complex 1 deficiency (PMID: 20571988). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by a clinical laboratory in ClinVar, however, this entry does not provide evidence for their classification. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Nov 24, 2024