Variant summary: NDUFS4 c.316C>T (p.Arg106X) 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 have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes (gnomAD). c.316C>T has been reported in the literature in multiple individuals affected with NADH-ubiquinone oxidoreductase (complex I) deficiency or combined complex I and III deficiency (Budde_2000, Voets_2012, Haack_2012). These data indicate that the variant is very likely to be associated with disease. In addition, this variant results in impaired cytosolic Ca2+ handling in complex I-deficient fibroblasts (Visch_2004, Voets_2012). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_002495.4(NDUFS4):c.316C>T (p.Arg106Ter)
Germline
Classification
Help
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.
(8)
Help
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002495.4(NDUFS4):c.316C>T (p.Arg106Ter)
Variation ID: 6889 Accession: VCV000006889.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q11.2 5: 52942201 (GRCh37) [ NCBI UCSC ] 5: 53646371 (GRCh38) [ 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 Feb 8, 2018 Jun 17, 2024 Dec 20, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002495.4:c.316C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002486.1:p.Arg106Ter nonsense NM_001318051.2:c.316C>T NP_001304980.1:p.Arg106Ter nonsense NR_134473.2:n.512C>T non-coding transcript variant NR_134474.2:n.429C>T non-coding transcript variant NR_134475.2:n.464C>T non-coding transcript variant NC_000005.10:g.53646371C>T NC_000005.9:g.52942201C>T NG_008200.1:g.90737C>T - Protein change
- R106*
- Other names
- -
- Canonical SPDI
- NC_000005.10:53646370: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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
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. |
|||
| NDUFS4 | - | - |
GRCh38 GRCh37 |
170 | 230 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 20, 2023 | RCV000735424.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 15, 2017 | RCV000578296.6 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 19, 2023 | RCV002298437.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2022 | RCV002307359.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Nov 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex I deficiency, nuclear type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680312.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: female
Tissue: blood
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex I deficiency, nuclear type 1
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426440.1
First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020 |
|
|
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Pathogenic
(Oct 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Leigh syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600857.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: NDUFS4 c.316C>T (p.Arg106X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NDUFS4 c.316C>T (p.Arg106X) 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 have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes (gnomAD). c.316C>T has been reported in the literature in multiple individuals affected with NADH-ubiquinone oxidoreductase (complex I) deficiency or combined complex I and III deficiency (Budde_2000, Voets_2012, Haack_2012). These data indicate that the variant is very likely to be associated with disease. In addition, this variant results in impaired cytosolic Ca2+ handling in complex I-deficient fibroblasts (Visch_2004, Voets_2012). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293730.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg106*) in the NDUFS4 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg106*) in the NDUFS4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFS4 are known to be pathogenic (PMID: 10944442, 16213125). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 10944442). ClinVar contains an entry for this variant (Variation ID: 6889). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Apr 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002588321.2
First in ClinVar: Nov 05, 2022 Last updated: Mar 04, 2023 |
Comment:
Functional studies conducted in patient cells demonstrate R106* exhibits morphogenesis defects as neurite outgrowth was decreased in immature neurons expressing the variant compared to wild … (more)
Functional studies conducted in patient cells demonstrate R106* exhibits morphogenesis defects as neurite outgrowth was decreased in immature neurons expressing the variant compared to wild type neural progenitor cells (Inak et al., 2021); 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: 25525159, 22033105, 10944442, 32860008, 33771987) (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 1
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046168.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This nonsense variant found in exon 3 of 5 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated … (more)
This nonsense variant found in exon 3 of 5 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous change in patients with mitochondrial complex I deficiency (PMID: 10944442). Functional studies have shown the presence of this variant results in a reduction of complex I enzymatic activity in skeletal muscle (PMID: 10944442). The c.316C>T (p.Arg106Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004 % (1/251396) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.316C>T (p.Arg106Ter) variant is classified as Pathogenic. (less)
|
|
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Pathogenic
(Dec 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial complex I deficiency, nuclear type 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005056237.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Aug 18, 2000)
|
no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027488.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 18, 2018 |
Comment on evidence:
In a patient with complex I deficiency and decreased complex III activity, Budde et al. (2000) identified a 316C-T transition of the NDUFS4 cDNA, causing … (more)
In a patient with complex I deficiency and decreased complex III activity, Budde et al. (2000) identified a 316C-T transition of the NDUFS4 cDNA, causing an arg106-to-stop amino acid change. The patient was homozygous for the mutation; his parents, who were consanguineous, and a brother were heterozygous. Except for hypospadias noted at birth, the patient appeared normal until the age of 7 weeks at which time muscular hypotonia and lack of visual and auditive attention were observed. At the age of 3 months he was found to have elevated lactate levels in the blood. Cranial MRI showed hyperintense signals resembling those found in Leigh syndrome (256000). Cardiac ultrasound showed concentric hypertrophy of the left ventricle with hypercontractility. He died from cardiocirculatory insufficiency. (less)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg106*) in the NDUFS4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFS4 are known to be pathogenic (PMID: 10944442, 16213125). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 10944442). ClinVar contains an entry for this variant (Variation ID: 6889). For these reasons, this variant has been classified as Pathogenic.
Comment:
Functional studies conducted in patient cells demonstrate R106* exhibits morphogenesis defects as neurite outgrowth was decreased in immature neurons expressing the variant compared to wild type neural progenitor cells (Inak et al., 2021); 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: 25525159, 22033105, 10944442, 32860008, 33771987)
Comment:
This nonsense variant found in exon 3 of 5 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous change in patients with mitochondrial complex I deficiency (PMID: 10944442). Functional studies have shown the presence of this variant results in a reduction of complex I enzymatic activity in skeletal muscle (PMID: 10944442). The c.316C>T (p.Arg106Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004 % (1/251396) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.316C>T (p.Arg106Ter) variant is classified as Pathogenic.
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. |
Comment:
Variant summary: NDUFS4 c.316C>T (p.Arg106X) 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 have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251396 control chromosomes (gnomAD). c.316C>T has been reported in the literature in multiple individuals affected with NADH-ubiquinone oxidoreductase (complex I) deficiency or combined complex I and III deficiency (Budde_2000, Voets_2012, Haack_2012). These data indicate that the variant is very likely to be associated with disease. In addition, this variant results in impaired cytosolic Ca2+ handling in complex I-deficient fibroblasts (Visch_2004, Voets_2012). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg106*) in the NDUFS4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFS4 are known to be pathogenic (PMID: 10944442, 16213125). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 10944442). ClinVar contains an entry for this variant (Variation ID: 6889). For these reasons, this variant has been classified as Pathogenic.
Comment:
Functional studies conducted in patient cells demonstrate R106* exhibits morphogenesis defects as neurite outgrowth was decreased in immature neurons expressing the variant compared to wild type neural progenitor cells (Inak et al., 2021); 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: 25525159, 22033105, 10944442, 32860008, 33771987)
Comment:
This nonsense variant found in exon 3 of 5 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous change in patients with mitochondrial complex I deficiency (PMID: 10944442). Functional studies have shown the presence of this variant results in a reduction of complex I enzymatic activity in skeletal muscle (PMID: 10944442). The c.316C>T (p.Arg106Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004 % (1/251396) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.316C>T (p.Arg106Ter) variant is classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9. | Haack TB | Journal of medical genetics | 2012 | PMID: 22200994 |
| Transcriptional changes in OXPHOS complex I deficiency are related to anti-oxidant pathways and could explain the disturbed calcium homeostasis. | Voets AM | Biochimica et biophysica acta | 2012 | PMID: 22033105 |
| Decreased agonist-stimulated mitochondrial ATP production caused by a pathological reduction in endoplasmic reticulum calcium content in human complex I deficiency. | Visch HJ | Biochimica et biophysica acta | 2006 | PMID: 16213125 |
| Inhibition of mitochondrial Na+-Ca2+ exchange restores agonist-induced ATP production and Ca2+ handling in human complex I deficiency. | Visch HJ | The Journal of biological chemistry | 2004 | PMID: 15269216 |
| Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene. | Budde SM | Biochemical and biophysical research communications | 2000 | PMID: 10944442 |
Text-mined citations for rs104893898 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.