ClinVar Genomic variation as it relates to human health
NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(6); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter)
Variation ID: 419231 Accession: VCV000419231.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q12.1 5: 60945369 (GRCh38) [ NCBI UCSC ] 5: 60241196 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 27, 2017 Oct 8, 2024 Jan 24, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_174889.5:c.114C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_777549.1:p.Tyr38Ter nonsense NC_000005.10:g.60945369C>G NC_000005.9:g.60241196C>G NG_008978.1:g.5241C>G NG_009289.1:g.4710G>C LRG_466:g.4710G>C - Protein change
- Y38*
- Other names
- -
- Canonical SPDI
- NC_000005.10:60945368:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
ERCC8 | - | - |
GRCh38 GRCh37 |
493 | 612 | |
NDUFAF2 | - | - |
GRCh38 GRCh37 |
128 | 185 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV000485122.6 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 28, 2023 | RCV000590864.7 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 23, 2018 | RCV000674200.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 21, 2018 | RCV000780529.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 12, 2018 | RCV001335554.1 | |
NDUFAF2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Apr 24, 2024 | RCV004735557.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Uncertain significance
(Apr 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cockayne syndrome type 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000799498.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
Pathogenic
(Nov 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917864.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: NDUFAF2 c.114C>G (p.Tyr38X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NDUFAF2 c.114C>G (p.Tyr38X) 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 has been classified as pathogenic by our laboratory (e.g. c.139C>T, p.Arg47X; c.221G>A, p.Trp74X). The variant allele was found at a frequency of 5.4e-05 in 277122 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NDUFAF2 causing Leigh Syndrome (5.4e-05 vs 0.0013), allowing no conclusion about variant significance. The variant, c.114C>G, has been reported in the literature in one homozygote individual affected with Leigh Syndrome (Hoefs_2009). These data indicate that the variant may be associated with disease. The same publication reports experimental evidence showing no NDUFAF2 protein expression in patient's fibroblasts and a marked decrease in complex I activity (to 21-23% of the lowest control value). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic x2, VUS x1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Dec 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex I deficiency, nuclear type 1
Affected status: yes
Allele origin:
maternal
|
Baylor Genetics
Accession: SCV001528725.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 19384974]
|
|
Pathogenic
(May 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000566903.6
First in ClinVar: Apr 27, 2017 Last updated: Jun 10, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19384974) (less)
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004291832.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr38*) in the NDUFAF2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr38*) in the NDUFAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFAF2 are known to be pathogenic (PMID: 18180188). This variant is present in population databases (rs199754807, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 19384974). ClinVar contains an entry for this variant (Variation ID: 419231). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Aug 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex 1 deficiency, nuclear type 10
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563745.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The NDUFAF2 c.114C>G; p.Tyr38Ter variant (rs199754807) is reported in the literature in a homozygous individual affected with mitochondrial complex I deficiency (Hoefs 2009). This variant … (more)
The NDUFAF2 c.114C>G; p.Tyr38Ter variant (rs199754807) is reported in the literature in a homozygous individual affected with mitochondrial complex I deficiency (Hoefs 2009). This variant is reported in ClinVar (Variation ID: 419231) and is found in the general population with an overall allele frequency of 0.005% (15/282,774 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and while mRNA studies of patient cells suggest this variant may escape nonsense-mediated decay, it is predicted to result in a truncated protein. Patient cells homozygous for this variant exhibit significantly decreased mitochondrial complex I activity (Hoefs 2009). Based on available information, this variant is considered to be pathogenic. References: Hoefs SJ et al. Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency. Hum Mutat. 2009 Jul;30(7):E728-36. PMID: 19384974. (less)
|
|
Pathogenic
(May 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex 1 deficiency, nuclear type 10
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557530.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
A heterozygous nonsense variant, NM_174889.4(NDUFAF2):c.114C>G, has been identified in exon 1 of 4 of the NDUFAF2 gene. The variant is predicted to result in a … (more)
A heterozygous nonsense variant, NM_174889.4(NDUFAF2):c.114C>G, has been identified in exon 1 of 4 of the NDUFAF2 gene. The variant is predicted to result in a premature stop codon at position 38 of the protein, NP_777549.1(NDUFAF2):p.(Tyr38*). This variant is predicted to result in loss of protein function through truncation (including the NDUFA12 domain), which is a reported mechanism of pathogenicity for this gene. The variant has been previously described as pathogenic and identified in a homozygous patient with complex I deficiency and clinical symptoms of Leigh disease (ClinVar, Hoefs, S. et al. (2009)). Additionally, functional studies showed a decrease in complex I activity in the cultured skin fibroblasts and a disturbance in the assembly of complex I (Hoefs, S. et al. (2009)). Other variants resulting in a truncated protein have been reported as pathogenic in this gene (ClinVar)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
|
|
Pathogenic
(Dec 13, 2018)
|
no assertion criteria provided
Method: literature only
|
MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 10
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000700072.2
First in ClinVar: Mar 20, 2018 Last updated: Dec 16, 2018 |
Comment on evidence:
In a girl, born of consanguineous parents, with fatal mitochondrial complex I deficiency (MC1DN10; 618233), Hoefs et al. (2009) identified a homozygous c.114C-G transversion (c.114C-G, … (more)
In a girl, born of consanguineous parents, with fatal mitochondrial complex I deficiency (MC1DN10; 618233), Hoefs et al. (2009) identified a homozygous c.114C-G transversion (c.114C-G, NM_174889.4) in exon 1 of the NDUFAF2 gene, predicted to result in a tyr38-to-ter (Y38X) substitution. The mutation was found by homozygosity mapping and candidate gene sequencing. Patient cells showed mRNA levels similar to controls, suggesting that the mutation escapes nonsense-mediated mRNA decay. However, Western blot analysis of patient cells showed no detectable NDUFAF2 protein. Patient fibroblasts showed a marked decrease in complex I activity (21-23% of controls) and evidence of disturbed assembly of complex I. These biochemical defects in the patient's cells could be rescued by a baculovirus containing the wildtype NDUFAF2 gene. The patient presented at 3 months of age with nystagmus. At age 7 months, she had vomiting, renal tubular acidosis, poor feeding, and evidence of neurologic decline, including hypotonia and delayed motor development. Laboratory studies showed mildly increased blood lactate, and brain imaging showed signal abnormalities in the thalamus, cerebral peduncles, brainstem, and spinal cord. She developed dyskinetic movements and central hyperventilation, resulting in death at 1 year of age. (less)
|
|
Pathogenic
(Apr 24, 2024)
|
no assertion criteria provided
Method: clinical testing
|
NDUFAF2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005360442.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The NDUFAF2 c.114C>G variant is predicted to result in premature protein termination (p.Tyr38*). This variant was reported in the homozygous state in an individual with … (more)
The NDUFAF2 c.114C>G variant is predicted to result in premature protein termination (p.Tyr38*). This variant was reported in the homozygous state in an individual with mitochondrial complex I deficiency (Hoefs et al. 2009. PubMed ID: 19384974). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in NDUFAF2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Dynamics of Human Mitochondrial Complex I Assembly: Implications for Neurodegenerative Diseases. | Giachin G | Frontiers in molecular biosciences | 2016 | PMID: 27597947 |
Mitochondrial complex I deficiency of nuclear origin II. Non-structural genes. | Pagniez-Mammeri H | Molecular genetics and metabolism | 2012 | PMID: 22099533 |
Understanding mitochondrial complex I assembly in health and disease. | Mimaki M | Biochimica et biophysica acta | 2012 | PMID: 21924235 |
Leigh disease with brainstem involvement in complex I deficiency due to assembly factor NDUFAF2 defect. | Herzer M | Neuropediatrics | 2010 | PMID: 20571988 |
Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency. | Hoefs SJ | Human mutation | 2009 | PMID: 19384974 |
The unique neuroradiology of complex I deficiency due to NDUFA12L defect. | Barghuti F | Molecular genetics and metabolism | 2008 | PMID: 18180188 |
Text-mined citations for rs199754807 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.