ClinVar Genomic variation as it relates to human health
NM_001135998.3(NDUFB11):c.361G>A (p.Glu121Lys)
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_001135998.3(NDUFB11):c.361G>A (p.Glu121Lys)
Variation ID: 372149 Accession: VCV000372149.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.3 X: 47142418 (GRCh38) [ NCBI UCSC ] X: 47001817 (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 Feb 14, 2024 Oct 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001135998.3:c.361G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001129470.1:p.Glu121Lys missense NM_019056.7:c.391G>A NP_061929.2:p.Glu131Lys missense NC_000023.11:g.47142418C>T NC_000023.10:g.47001817C>T NG_012548.1:g.2187C>T NG_052579.1:g.7793G>A - Protein change
- E121K, E131K
- Other names
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- Canonical SPDI
- NC_000023.11:47142417: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.
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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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NDUFB11 | - | - |
GRCh38 GRCh37 |
61 | 215 |
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
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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) |
no assertion criteria provided
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Dec 13, 2018 | RCV000412600.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 5, 2023 | RCV000487272.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 2, 2022 | RCV002272220.2 |
Submissions - Germline
Classification
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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
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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
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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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Likely pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Linear skin defects with multiple congenital anomalies 3
(X-linked dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557187.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 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 X-linked dominant linear skin defects with multiple congenital anomalies 3 (MIM#300952) and X-linked recessive nuclear type 30 mitochondrial complex I deficiency (MIM#301021). Affected females have been reported with heterozygous null alleles, whereas affected males have only been identified with missense and single residue in-frame deletions, suggesting that some residual enzyme activity is required for males to be viable, whereas complete loss of function variants may be lethal when hemizygous (PMID: 30423443). (I) 0110 - This gene is associated with X-linked disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Affected females have previously been reported to inherit pathogenic variants from their unaffected mothers. It has been suggested that this may be due to patterns of somatic X-chromosome inactivation, mosaicism or additional genetic and external factors (PMID: 28050600). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable syndromic features have been observed in affected individuals. However, anaemia and cardiomyopathy appear to be consistent features in males and females, respectively (PMID: 28050600, PMID: 30423443, PMID: 27488349). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ESSS subunit of NADH:ubiquinone oxidoreductase (complex I) (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has previously been classified as pathogenic in ClinVar, and has been reported de novo in a hemizygous male with lethal infantile mitochondrial disorder (PMID: 26741492). Additionally, the variant has been observed in a mother and daughter affected with left ventricular noncompaction (PMID: 31243186); it was not considered to be causative as they did not present with a metabolic disorder, however, the mitochondrial features of NDUFB11-related disease are known to only present in hemizygous males (PMID: 25772934, PMID: 30423443). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Western blots using patient fibroblasts demonstrated no detectable NDUFB11 protein, consistent with a complete loss of function (PMID: 26741492). (SP) 1207 - Parental origin of the variant is unresolved. Testing of this individual's mother did not confirm maternal inheritance. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(May 07, 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: SCV000569992.5
First in ClinVar: Apr 27, 2017 Last updated: May 13, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25772934, 26741492, 31243186, 28050600, 30423443, 27488349, 36675256, 33233646, 31332208) (less)
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Pathogenic
(Oct 05, 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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Invitae
Accession: SCV004269346.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 131 of the NDUFB11 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 131 of the NDUFB11 protein (p.Glu131Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of NDUFB11-related conditions (PMID: 26741492, 31243186, 36252119). In at least one individual the variant was observed to be de novo. This variant is also known as p.E121K. ClinVar contains an entry for this variant (Variation ID: 372149). 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 NDUFB11 function (PMID: 26741492). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 13, 2018)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 30 (1 patient)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000490221.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 16, 2018 |
Comment on evidence:
In a male infant (patient 067) with lethal mitochondrial complex I deficiency nuclear type 30 (MC1DN30; 301021), Kohda et al. (2016) identified a de novo … (more)
In a male infant (patient 067) with lethal mitochondrial complex I deficiency nuclear type 30 (MC1DN30; 301021), Kohda et al. (2016) identified a de novo hemizygous c.361G-A transition (c.361G-A, NM_001135998) in the NDUFB11 gene, resulting in a glu121-to-lys (E121K) substitution at a highly conserved residue. The mutation was found by high-throughput exome sequencing and confirmed by Sanger sequencing. The variant was filtered against the dbSNP (build 137), Exome Sequencing Project (ESP6500), and ExAC (February 2014) databases. Western blot analysis of patient fibroblasts showed no detectable NDUFB11 protein. Knockdown of the Ndufb11 gene in Drosophila resulted in significantly reduced lifespan, decreased metabolic rate, loss of mitochondrial complex I assembly, and increased lactate and pyruvate. The patient had intrauterine growth restriction, premature birth, heart failure, respiratory failure, metabolic acidosis, and mitochondrial complex I deficiency; he died at 55 hours of age. He had redundant skin but no linear skin defects. (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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Genetic Basis of Childhood Cardiomyopathy. | Bagnall RD | Circulation. Genomic and precision medicine | 2022 | PMID: 36252119 |
Familial Left Ventricular Non-Compaction Is Associated With a Rare p.V407I Variant in Bone Morphogenetic Protein 10. | Hirono K | Circulation journal : official journal of the Japanese Circulation Society | 2019 | PMID: 31243186 |
Diverse phenotype in patients with complex I deficiency due to mutations in NDUFB11. | Reinson K | European journal of medical genetics | 2019 | PMID: 30423443 |
Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11. | Rea G | Cold Spring Harbor molecular case studies | 2017 | PMID: 28050600 |
A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia. | Lichtenstein DA | Blood | 2016 | PMID: 27488349 |
A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. | Kohda M | PLoS genetics | 2016 | PMID: 26741492 |
Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome. | van Rahden VA | American journal of human genetics | 2015 | PMID: 25772934 |
Text-mined citations for rs1057519073 ...
HelpRecord last updated Feb 20, 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.