ClinVar Genomic variation as it relates to human health
NM_024120.5(NDUFAF5):c.327G>C (p.Lys109Asn)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024120.5(NDUFAF5):c.327G>C (p.Lys109Asn)
Variation ID: 265061 Accession: VCV000265061.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p12.1 20: 13788652 (GRCh38) [ NCBI UCSC ] 20: 13769298 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 10, 2016 May 12, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024120.5:c.327G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_077025.2:p.Lys109Asn missense NM_001039375.3:c.327G>C NP_001034464.1:p.Lys109Asn missense NM_001352403.2:c.-41G>C 5 prime UTR NM_001352406.2:c.-255G>C 5 prime UTR NM_001352407.2:c.-235G>C 5 prime UTR NM_001352408.2:c.327G>C NP_001339337.1:p.Lys109Asn missense NR_029377.2:n.368G>C non-coding transcript variant NR_147978.2:n.368G>C non-coding transcript variant NR_147979.2:n.368G>C non-coding transcript variant NR_147980.2:n.368G>C non-coding transcript variant NR_147981.2:n.502G>C non-coding transcript variant NR_147982.2:n.502G>C non-coding transcript variant NR_147983.2:n.502G>C non-coding transcript variant NC_000020.11:g.13788652G>C NC_000020.10:g.13769298G>C NG_015811.1:g.8627G>C - Protein change
- K109N
- Other names
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- Canonical SPDI
- NC_000020.11:13788651:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00028
Trans-Omics for Precision Medicine (TOPMed) 0.00036
The Genome Aggregation Database (gnomAD), exomes 0.00045
Exome Aggregation Consortium (ExAC) 0.00055
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
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 | ||
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HI score
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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. |
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NDUFAF5 | - | - |
GRCh38 GRCh38 GRCh37 |
390 | 522 |
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. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000255420.24 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2023 | RCV001507283.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 27, 2018 | RCV001266325.4 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jul 19, 2021 | RCV001833296.3 | |
not provided (1) |
no classification provided
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- | RCV001824717.3 |
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. |
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Likely pathogenic
(Mar 27, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444499.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Sep 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321490.8
First in ClinVar: Oct 10, 2016 Last updated: Sep 30, 2023 |
Comment:
In silico splice predictors support a deleterious effect and published RNA functional studies demonstrate a damaging splicing effect with skipping of exon 3 (Simon et … (more)
In silico splice predictors support a deleterious effect and published RNA functional studies demonstrate a damaging splicing effect with skipping of exon 3 (Simon et al., 2019); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 30473481, 30581749, 33586140, 27817865, 34177781, 29261183, 34858319, 34964562) (less)
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Likely pathogenic
(Nov 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000493172.28
First in ClinVar: Oct 10, 2016 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 16
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004191996.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Nov 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 16
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003814510.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002305404.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 109 of the NDUFAF5 protein (p.Lys109Asn). … (more)
This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 109 of the NDUFAF5 protein (p.Lys109Asn). This variant is present in population databases (rs150613320, gnomAD 0.2%). This missense change has been observed in individual(s) with Leigh syndrome (PMID: 30473481). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265061). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NDUFAF5 function (PMID: 30473481). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Jun 07, 2021)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 16
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001712103.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment on evidence:
In a Caucasian patient (patient 3) with deficiencies of mitochondrial complexes I and IV (MC1DN16; 618238), Simon et al. (2019) identified compound heterozygous mutations in … (more)
In a Caucasian patient (patient 3) with deficiencies of mitochondrial complexes I and IV (MC1DN16; 618238), Simon et al. (2019) identified compound heterozygous mutations in the NDUFAF5 gene: a c.327G-C transversion (c.327G-C, NM_024120) in exon 3, resulting in a lys109-to-asn (K109N) substitution, and a c.223-907A-C splicing mutation in intron 1 (612360.0008). The K109N mutation had an allele frequency of 0.0007 in the non-Finnish European population in the gnomAD database. The mutations were identified by a combination of whole-exome and whole-genome sequencing, and the parents were shown to be carriers. Amplification and sequencing of RNA from patient fibroblasts and maternal blood showed that the c.327G-C transversion results in abnormal splicing with skipping of exon 3, leading to a frameshift and early termination. Amplification and sequencing of RNA from patient fibroblasts and paternal blood showed that the splice site mutation results in the inclusion of a 258-bp cryptic exon. Patient fibroblasts showed NDUFAF5 mRNA levels decreased to 25 to 40% of normal. For discussion of the K109N mutation that was found in compound heterozygous state in an Ashkenazi Jewish patient (patient 4) with MC1DN16 by Simon et al. (2019), see 612360.0003. (less)
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Likely pathogenic
(Jul 19, 2021)
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no assertion criteria provided
Method: clinical testing
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Mitochondrial complex I deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002090909.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Mitochondrial complex I deficiency, nuclear type 1
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002074967.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
Variant interpreted as Likely pathogenic and reported on 05-24-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpreted as Likely pathogenic and reported on 05-24-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Pregnancy history (present) , Short stature (present) , Abnormal facial shape (present) , Abnormal oral cavity morphology (present) , Oral-pharyngeal dysphagia (present) , Abnormality of … (more)
Pregnancy history (present) , Short stature (present) , Abnormal facial shape (present) , Abnormal oral cavity morphology (present) , Oral-pharyngeal dysphagia (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Generalized hypotonia (present) , Seizure (present) , Short attention span (present) , Abnormality of facial musculature (present) , Abnormal muscle physiology (present) , Abnormal pattern of respiration (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , Abnormal large intestine morphology (present) , Recurrent infections (present) , Abnormal dental morphology (present) , Abnormality of primary teeth (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-05-24
Testing laboratory interpretation: Likely pathogenic
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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 |
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Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes. | Simon MT | Molecular genetics and metabolism | 2019 | PMID: 30473481 |
Revisiting mitochondrial diagnostic criteria in the new era of genomics. | Witters P | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29261183 |
Text-mined citations for rs150613320 ...
HelpRecord last updated May 12, 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.