This sequence change creates a premature translational stop signal (p.Trp97*) 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 Leigh syndrome (PMID: 10944442, 27079373). ClinVar contains an entry for this variant (Variation ID: 6888). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_002495.4(NDUFS4):c.291del (p.Lys96_Trp97insTer)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002495.4(NDUFS4):c.291del (p.Lys96_Trp97insTer)
Variation ID: 6888 Accession: VCV000006888.7
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 5q11.2 5: 53646345 (GRCh38) [ NCBI UCSC ] 5: 52942175 (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 Apr 27, 2017 Sep 16, 2024 Sep 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002495.4:c.291del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002486.1:p.Lys96_Trp97insTer nonsense NM_001318051.2:c.291del NP_001304980.1:p.Lys96_Trp97insTer nonsense NM_002495.2:c.291del NR_134473.2:n.487del non-coding transcript variant NR_134474.2:n.404del non-coding transcript variant NR_134475.2:n.439del non-coding transcript variant NC_000005.10:g.53646346del NC_000005.9:g.52942176del NG_008200.1:g.90712del - Protein change
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- Other names
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W96*
- Canonical SPDI
- NC_000005.10:53646344:GG:G
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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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- 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 |
171 | 231 | |
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, single submitter
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Mar 27, 2024 | RCV000007291.4 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2024 | RCV000484109.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 6, 2022 | RCV002307358.1 |
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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Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293729.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp97*) 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.Trp97*) 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 Leigh syndrome (PMID: 10944442, 27079373). ClinVar contains an entry for this variant (Variation ID: 6888). For these reasons, this variant has been classified as Pathogenic. (less)
|
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Pathogenic
(Oct 06, 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: SCV002600322.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: NDUFS4 c.291delG (p.Trp97X) 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.291delG (p.Trp97X) 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 was absent in 251386 control chromosomes. c.291delG has been reported in the literature in multiple individuals affected with Leigh Syndrome (Assouline_2012, Jou_2019, Budde_2000). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
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Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex I deficiency, nuclear type 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005056234.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Sep 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000566768.5
First in ClinVar: Apr 27, 2017 Last updated: Sep 16, 2024 |
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 … (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: 27126960, 12944388, 10944442, 27374853, 27079373, 27671926, 26024641, 30634555, 14765537, 16213125, 22326555) (less)
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Pathogenic
(Aug 18, 2000)
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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: SCV000027487.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 16, 2018 |
Comment on evidence:
Budde et al. (2000) demonstrated mutations in the NDUFS4 gene of patients with complex I deficiency nuclear type 1 (MC1DN1; 252010) and decreased activity of … (more)
Budde et al. (2000) demonstrated mutations in the NDUFS4 gene of patients with complex I deficiency nuclear type 1 (MC1DN1; 252010) and decreased activity of complex III. The first mutation was a homozygous 1-bp deletion of G at position 289 or 290, resulting in a trp96-to-ter (W96X) substitution. Both parents were heterozygous for the mutation. The female patient showed, within 1 week of age, hypotonia, absent eye contact, lethargy, and failure to thrive. At 3 months of age, microcephaly was present and lactic acidemia with an increased lactate/pyruvate ratio was found. CT and MRI showed bilateral basal ganglia hypodensities. The child died at 3 months of age. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035290.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002034204.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
Comment:
Comment:
Variant summary: NDUFS4 c.291delG (p.Trp97X) 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 was absent in 251386 control chromosomes. c.291delG has been reported in the literature in multiple individuals affected with Leigh Syndrome (Assouline_2012, Jou_2019, Budde_2000). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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 observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27126960, 12944388, 10944442, 27374853, 27079373, 27671926, 26024641, 30634555, 14765537, 16213125, 22326555)
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:
This sequence change creates a premature translational stop signal (p.Trp97*) 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 Leigh syndrome (PMID: 10944442, 27079373). ClinVar contains an entry for this variant (Variation ID: 6888). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: NDUFS4 c.291delG (p.Trp97X) 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 was absent in 251386 control chromosomes. c.291delG has been reported in the literature in multiple individuals affected with Leigh Syndrome (Assouline_2012, Jou_2019, Budde_2000). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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 observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27126960, 12944388, 10944442, 27374853, 27079373, 27671926, 26024641, 30634555, 14765537, 16213125, 22326555)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Muscle Involvement in a Large Cohort of Pediatric Patients with Genetic Diagnosis of Mitochondrial Disease. | Jou C | Journal of clinical medicine | 2019 | PMID: 30634555 |
| Ndufs4 related Leigh syndrome: A case report and review of the literature. | Ortigoza-Escobar JD | Mitochondrion | 2016 | PMID: 27079373 |
| A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome. | Assouline Z | Biochimica et biophysica acta | 2012 | PMID: 22326555 |
| 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 |
| Clinical heterogeneity in patients with mutations in the NDUFS4 gene of mitochondrial complex I. | Budde SM | Journal of inherited metabolic disease | 2003 | PMID: 14765537 |
| 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 rs121908985 ...
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 Nov 25, 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.