ClinVar Genomic variation as it relates to human health
NM_152416.4(NDUFAF6):c.298-768T>C
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(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_152416.4(NDUFAF6):c.298-768T>C
Variation ID: 917900 Accession: VCV000917900.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q22.1 8: 95034686 (GRCh38) [ NCBI UCSC ] 8: 96046914 (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 Jun 19, 2020 Jul 23, 2024 Jul 17, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- IVS2AS, T-C, -768 (rs575462405)
- Canonical SPDI
- NC_000008.11:95034685:T: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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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00007
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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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NDUFAF6 | - | - |
GRCh38 GRCh37 |
188 | 317 |
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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Uncertain significance (2) |
criteria provided, single submitter
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Jul 17, 2023 | RCV001175176.3 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 24, 2023 | RCV001875774.6 |
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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Uncertain significance
(May 19, 2022)
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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: SCV002756709.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Comment:
Observed in the apparent homozygous state in affected individuals from multiple Acadian families with a variant of Fanconi syndrome (Hartmannova et al., 2016); Published functional … (more)
Observed in the apparent homozygous state in affected individuals from multiple Acadian families with a variant of Fanconi syndrome (Hartmannova et al., 2016); Published functional studies demonstrate a damaging effect: aberrant splicing, loss of expression in mitochondria, and reduced activity of complex I (Hartmannova H et al., 2016); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 34426522, 27466185) (less)
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Pathogenic
(Feb 24, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002240899.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 2 of the NDUFAF6 gene. It does not directly change the encoded amino acid sequence of the NDUFAF6 protein. … (more)
This sequence change falls in intron 2 of the NDUFAF6 gene. It does not directly change the encoded amino acid sequence of the NDUFAF6 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Fanconi syndrome (PMID: 27466185). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 917900). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 27466185). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Jul 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fanconi renotubular syndrome 5
(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: SCV005087021.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. 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 17 (MIM#618239) and there is limited evidence for an association with Fanconi renotubular syndrome 5 (MIM#618913). (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. RT-PCR studies support aberrant splicing particularly when this variant is on the same haplotype as the c.298-731A>G polymorphism (PMID: 27466185). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3 - 7 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. PMID: 27466185 report this variant as homozygous in ten affected individuals from seven families in a founder ethnic sub-population (Acadian, Eastern Canada). Affected individuals had renal Fanconi syndrome and pulmonary fibrosis with no other features associated with mitochondrial complex I deficiency, nuclear type 17 (MIM#618239). This variant has also been reported in ClinVar as a VUS (GeneDx) and pathogenic (Invitae) and was identified as a single heterozygous variant in individuals with diverse, unrelated phenotypes. (SP) 0906 - Segregation evidence for this variant is inconclusive. PMID: 27466185 report this variant as homozygous in ten affected individuals; however, this variant was also noted as homozygous in one unaffected individual. Parental testing results were not provided for most affected individuals. There is also no information available regarding the prevalence of this haplotype in the Acadian community. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. NDFUFAF6 mitochondrial isoform (V_1) was shown to be depleted in affected skin fibroblasts and lung tissue with reduction in mitochondrial complex I subunuits (PMID: 27466185). (SP) 1205 - This variant has been shown to be maternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jun 16, 2020)
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no assertion criteria provided
Method: literature only
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FANCONI RENOTUBULAR SYNDROME 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001338775.1
First in ClinVar: Jun 19, 2020 Last updated: Jun 19, 2020 |
Comment on evidence:
In 12 affected individuals from 7 Acadian families with Fanconi renotubular syndrome-5 (FRTS5; 618913), also known as the Acadian variant of FRTS, Hartmannova et al. … (more)
In 12 affected individuals from 7 Acadian families with Fanconi renotubular syndrome-5 (FRTS5; 618913), also known as the Acadian variant of FRTS, Hartmannova et al. (2016) identified a homozygous intronic mutation (chr8.96,046,914T-C, GRCh37) in the NDUFAF6 gene. The mutation was identified by exome sequencing/homozygosity mapping or genome sequencing and was confirmed in 9 patients by Sanger sequencing. The mutations segregated with disease in all of the families; 13 healthy sibs were either heterozygous or lacked the mutation, but sequencing of the unaffected parents was not reported. The variant was absent from the Kaviar database and was found once among 104 individuals from a Puerto Rican sample set analyzed from the 1000 Genome Project database. The intronic mutation creates a novel splice acceptor site and affects splicing and synthesis of NDUFAF6 isoforms, leading to a loss of the mitochondria-associated NDUFAF6 isoform. Studies in mitochondria from patient lung tissue or fibroblasts showed decreased complex I expression and in-gel activity. These defects were corrected in fibroblasts by transfection of wildtype NDUFAF6. (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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Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6. | Hartmannová H | Human molecular genetics | 2016 | PMID: 27466185 |
Text-mined citations for rs575462405 ...
HelpRecord last updated Sep 29, 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.