ClinVar Genomic variation as it relates to human health
NM_001086521.2(NDUFAF8):c.195+271C>T
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_001086521.2(NDUFAF8):c.195+271C>T
Variation ID: 691642 Accession: VCV000691642.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 81239949 (GRCh38) [ NCBI UCSC ] 17: 79213749 (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 Dec 23, 2019 Oct 8, 2024 Aug 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001086521.2:c.195+271C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001353402.1:c.199+267C>T intron variant NM_001353403.1:c.37+6C>T intron variant NR_148426.1:n.36C>T non-coding transcript variant NC_000017.11:g.81239949C>T NC_000017.10:g.79213749C>T - Protein change
- Other names
- IVS2, C-T, +271
- Canonical SPDI
- NC_000017.11:81239948:C:T
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00060
The Genome Aggregation Database (gnomAD) 0.00063
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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NDUFAF8 | - | - |
GRCh38 GRCh37 |
10 | 38 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (1) |
criteria provided, single submitter
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Oct 9, 2019 | RCV000984080.2 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2022 | RCV001003490.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 1, 2024 | RCV002275160.15 | |
NDUFAF8-related disorder
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Likely pathogenic (1) |
no assertion criteria provided
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Jun 6, 2024 | RCV004754579.1 |
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
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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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Pathogenic
(Oct 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial disease
Affected status: yes
Allele origin:
germline
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Wellcome Centre for Mitochondrial Research, Newcastle University
Accession: SCV000995083.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
Number of individuals with the variant: 2
Sex: male
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Likely pathogenic
(May 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 34
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001737627.1
First in ClinVar: Jun 23, 2021 Last updated: Jun 23, 2021 |
Comment:
Variant summary: C17ORF89 (NDUFAF8) c.195+271C>T is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on … (more)
Variant summary: C17ORF89 (NDUFAF8) c.195+271C>T is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic intronic 5 donor site. Experimental evidence demonstrated this variant was associated with an mRNA defect leading to loss of the functionally relevant transcript (Alston_2020). The variant allele was found at a frequency of 0.00062 in 150992 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD v3.1.1 database. Due to an unknown prevalence of C17ORF89 associated Mitochondrial Complex 1 Deficiency, this frequency relative to that expected for a pathogenic variant in C17ORF89 is unknown, allowing no conclusion about variant significance. c.195+271C>T has been reported in the literature in two comprehensively genotyped compound heterozygous individuals affected with Mitochondrial Complex 1 Deficiency (Alston_2020). Experimental evidence derived from studies on fibroblasts and muscle cells from one of these individuals indicated a decrease in complex I activity, a reduction in oxidative capacity, decreased levels of fully assembled complex I and a generalized reduction in complex I subunits (Alston_2020). These data indicate that the variant may be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Mar 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 34
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV002523170.1 First in ClinVar: Jun 10, 2022 Last updated: Jun 10, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Oligohydramnios (present) , Bradycardia (present) , Premature birth following premature rupture of fetal membranes (present) , Prolonged neonatal jaundice (present) , Severe intrauterine growth retardation … (more)
Oligohydramnios (present) , Bradycardia (present) , Premature birth following premature rupture of fetal membranes (present) , Prolonged neonatal jaundice (present) , Severe intrauterine growth retardation (present) , Abnormal vascular physiology (present) , Induced vaginal delivery (present) , Exotropia (present) , Blindness (present) , Seizure (present) , Global developmental delay (present) , Failure to thrive (present) , Failure to thrive in infancy (present) , Bicuspid aortic valve (present) , Ventriculomegaly (present) , Abnormal basal ganglia morphology (present) , Delayed CNS myelination (present) , Hypoplasia of the brainstem (present) , Developmental regression (present) , Increased CSF lactate (present) , Abnormal cerebral white matter morphology (present) , Hypsarrhythmia (present) , Elevated circulating creatine kinase concentration (present) , Short stature (present) , Decreased body weight (present) , Dysplastic corpus callosum (present) , Abnormal thalamus morphology (present) , Epileptic spasm (present) , Bilateral multifocal epileptiform discharges (present) , EEG with generalized sharp slow waves (present) , EEG with occipital slowing (present) , Nasogastric tube feeding in infancy (present) , Infantile spasms (present) , Abnormal optic chiasm morphology (present) , Abnormal lateral ventricle morphology (present) , Colpocephaly (present) , Cerebral visual impairment (present) , Enlarged sylvian cistern (present) (less)
Age: 0-9 years
Sex: female
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Likely pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 34
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769042.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 34 (MIM#618776). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Functional analysis of patient fibroblasts shows this variant results in intron retention and the loss of isoform 2. However, the exact protein outcome is unclear as this would be expected to result in a truncated protein (PMID: 31866046). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (93 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable intronic variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been described as likely pathogenic and pathogenic, and observed in two unrelated compound heterozygous individuals with Leigh syndrome and complex I deficiency (ClinVar, PMID: 31866046). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Mar 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 34
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003836428.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Likely pathogenic
(Aug 01, 2024)
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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: SCV002563447.15
First in ClinVar: Aug 23, 2022 Last updated: Oct 08, 2024 |
Comment:
NDUFAF8: PM3:Strong, PM2, PS3:Supporting
Number of individuals with the variant: 2
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Pathogenic
(Apr 07, 2020)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 34
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001161786.2
First in ClinVar: Feb 23, 2020 Last updated: Apr 15, 2020 |
Comment on evidence:
In 2 unrelated patients (patients 1 and 2) with mitochondrial complex I deficiency nuclear type 34 (MC1DN34; 618776), Alston et al. (2020) identified compound heterozygous … (more)
In 2 unrelated patients (patients 1 and 2) with mitochondrial complex I deficiency nuclear type 34 (MC1DN34; 618776), Alston et al. (2020) identified compound heterozygous mutations in the NDUFAF8 gene. Both patients carried a C-to-T transition deep in intron 1 (c.195+271C-T, NM_001086521.1); patient 1 also carried an 8-bp duplication (c.45_52dup; 618461.0002) in exon 1, predicted to result in a frameshift and premature termination (Phe18SerfsTer32), and patient 2 also carried a c.1A-to-G transition (618461.0003), predicted to disrupt the translation initiation codon. The mutations were found by a combination of targeted sequencing and whole-exome sequencing; obligate carriers were noted, but sequence analysis of family members was not reported. Skeletal muscle and skin fibroblasts derived from patient 1 showed reduced complex I activity at 33% and 47% of controls, respectively, as well as decreased levels of fully assembled complex I and reduced oxidative capacity. Patient fibroblasts showed evidence of aberrant splicing, with loss of the functional isoform 2 transcript and expression of only the nonfunctional isoform 3 transcript. Other OXPHOS complexes were unaffected, although there was a decrease in the associated subunit NDUFAF5 (612360). Introduction of wildtype NDUFAF8 into patient cells rescued the defects. Tissue samples from patient 2 were not available. (less)
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Likely pathogenic
(Jun 06, 2024)
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no assertion criteria provided
Method: clinical testing
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NDUFAF8-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005345606.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The NDUFAF8 c.199+267C>T variant is predicted to interfere with splicing. This variant, also reported as c.195+271C>T in transcript NM_001086521, has been reported in two unrelated … (more)
The NDUFAF8 c.199+267C>T variant is predicted to interfere with splicing. This variant, also reported as c.195+271C>T in transcript NM_001086521, has been reported in two unrelated individuals with a clinical diagnosis of Leigh syndrome (subjects 1 and 2, Alston et al. 2019. PubMed ID: 31866046). In vitro studies from subject 1's fibroblast cells demonstrated expression of this variant results in aberrant splicing, a reduction in oxidative capacity, as well as decreased levels of fully assembled complex I in both muscle cells and fibroblasts compared to controls (Figures S3, S4 and 3, Alston et al. 2019. PubMed ID: 31866046). Additionally, a rescue assay demonstrated that this phenotype could be corrected by a reintroduction of wildtype (Figure 3, Alston et al. 2019. PubMed ID: 31866046). This variant is reported in 0.12% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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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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Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency. | Alston CL | American journal of human genetics | 2020 | PMID: 31866046 |
Text-mined citations for rs745332456 ...
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.