ClinVar Genomic variation as it relates to human health
NM_025152.3(NUBPL):c.815-27T>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(3); Likely pathogenic(4); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_025152.3(NUBPL):c.815-27T>C
Variation ID: 50317 Accession: VCV000050317.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q12 14: 31850092 (GRCh38) [ NCBI UCSC ] 14: 32319298 (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 Mar 8, 2017 May 1, 2024 Feb 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_025152.3:c.815-27T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001201573.2:c.527-27T>C intron variant NM_001201574.2:c.266-27T>C intron variant NC_000014.9:g.31850092T>C NC_000014.8:g.32319298T>C NG_028349.1:g.293708T>C - Protein change
- Other names
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- Canonical SPDI
- NC_000014.9:31850091: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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0.00200 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00172
1000 Genomes Project 0.00200
Trans-Omics for Precision Medicine (TOPMed) 0.00228
The Genome Aggregation Database (gnomAD), exomes 0.00345
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00348
The Genome Aggregation Database (gnomAD) 0.00348
Exome Aggregation Consortium (ExAC) 0.00373
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
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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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NUBPL | - | - |
GRCh38 GRCh37 |
262 | 299 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 1, 2023 | RCV000198391.26 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 13, 2021 | RCV000210589.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 16, 2024 | RCV000660543.9 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Jan 8, 2024 | RCV001249675.19 |
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
(Aug 14, 2017)
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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: SCV000251972.10
First in ClinVar: Oct 11, 2015 Last updated: Dec 19, 2017 |
Comment:
Expression studies of the c.815-27 T>C sequence change found that this variant impairs mRNA splicing resulting in a 80% decrease in complex I assembly and … (more)
Expression studies of the c.815-27 T>C sequence change found that this variant impairs mRNA splicing resulting in a 80% decrease in complex I assembly and function (Tucker et al., 2012; Wydro et al., 2013). Therefore, based on the currently available information, the c.815-27 T>C variant is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded. (less)
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Likely pathogenic
(May 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex I deficiency, nuclear type 1
Affected status: unknown
Allele origin:
maternal
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782648.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 21
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517825.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 21
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511894.2
First in ClinVar: May 16, 2022 Last updated: Aug 26, 2023 |
Comment:
Variant summary: NUBPL c.815-27T>C is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. … (more)
Variant summary: NUBPL c.815-27T>C is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, at least two publications report experimental evidence that this variant affects mRNA splicing (Tucker_2012, Kimonis_2021). The variant allele was found at a frequency of 0.0034 in 248676 control chromosomes in the gnomAD database, including 10 homozygotes. c.815-27T>C has been reported in the literature in multiple individuals affected with Mitochondrial Complex 1 Deficiency, Nuclear Type 21 (Calvo_2010, Kevelam_2013, Kimonis_2021), and some were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein expression, finding that a heterozygous control with the variant exhibited far lower expression of NUBPL protein (Tucker_2012). The following publications have been ascertained in the context of this evaluation (PMID: 20818383, 23553477, 22072591, 32518176). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=8) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Uncertain significance
(Feb 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000493198.27
First in ClinVar: Oct 09, 2016 Last updated: Apr 15, 2024 |
Comment:
NUBPL: PM3:Strong, PS3:Moderate, PM2:Supporting, PP3, BS2
Number of individuals with the variant: 3
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Uncertain Significance
(Feb 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex I deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847434.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.815-27T>C variant in NUBPL is typically observed as a compound allele (in cis) with the c.166G>A [p.G56R] variant in individuals with mitochondrial complex I … (more)
The c.815-27T>C variant in NUBPL is typically observed as a compound allele (in cis) with the c.166G>A [p.G56R] variant in individuals with mitochondrial complex I deficiency. By itself, it has been reported in at least one individual with mitochondrial complex I deficiency and an another variant in trans, and segregated with disease in at least 1 sibling (Kimonis 2021 PMID: 32518176; Maclean 2018 PMID:29982452). This variant has also been identified in 1.28% (819/63974) of European (Finnish) chromosomes, including 22 homozygotes, by gnomAD (http://gnomad.broadinstitute.org, v4.0.0) and reported in ClinVar (Variation ID 50317). This variant is located in the splice branch site, and computational prediction tools suggest an impact on splicing. An RT-PCR study demonstrated that this variant results in three transcripts: wild-type, the use of a cryptic acceptor site (p.G272VfsX11), or skipping of exon 10 (p.D273QfsX31). In addition, in vitro functional studies demonstrated that patient cells express reduced levels of the wild-type transcript, possibly as a result of degradation of a variant transcript by NMD (Tucker 2012 PMID: 22072591). Overall, it is unclear if this variant in isolation causes disease or whether it acts in synergy with the p.G56R variant. Therefore, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PP1, PP3, PS3_Supporting, BS1_Supporting. (less)
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Likely pathogenic
(Apr 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000262906.8
First in ClinVar: Apr 09, 2016 Last updated: May 01, 2024 |
Comment:
The c.815-27T>C intronic alteration consists of a T to C substitution 27 nucleotides before coding exon 10 in the NUBPL gene and is predicted to … (more)
The c.815-27T>C intronic alteration consists of a T to C substitution 27 nucleotides before coding exon 10 in the NUBPL gene and is predicted to affect the native branch site. Based on data from the Genome Aggregation Database (gnomAD) database, the NUBPL c.815-27T>C alteration was observed in 0.35% (992/280082) of total alleles studied (including 10 homozygotes), with a frequency of 1.24% (310/24978) in the European (Finnish) subpopulation. The [c.166G>A (p.G56R); c.815-27T>C] complex allele has been reported in the homozygous state, compound heterozygous state, and confirmed in trans with a second pathogenic allele in multiple unrelated patients with mitochondrial encephalomyopathy (Calvo, 2010; Kevelam, 2013). Emerging evidence is suggestive that the NUBPL [c.166G>A (p.G56R); c.815-27T>C] complex allele is likely pathogenic when these alterations are in cis; however, the clinical significance of these alterations in isolation remains uncertain. The c.815-27T nucleotide is highly conserved in available vertebrate species. Functional analysis of cultured fibroblasts from a patient bearing the [c.166G>A (p.G56R); c.815-27T>C] complex allele in trans with a complex rearrangement, as well as a control patient who was heterozygous for only the c.815-27T>C alteration, demonstrated an aberrant RT-PCR pattern with three distinct transcripts: wild-type, a lengthened transcript resulting from a cryptic splice site which introduces an additional 72 bp and results in a frameshift (p.G272Vfs*11), as well as a truncated transcript generated due to exon 10 skipping resulting in a frameshift (p.D273Qfs*31) (Tucker, 2012). Analysis by qRT-PCR and Western blot showed that the heterozygous control with only the c.815-27T>C alteration had reduced mRNA expression (74%) and protein expression (59%) compared to wild type controls, and the patient with the [c.166G>A (p.G56R); c.815-27T>C] complex allele and complex rearrangement on the other allele had more significant reduction in mRNA expression (15%) and undetectable protein expression (Tucker, 2012). No defective function was identified when the protein with the G56R missense change was over-expressed (Tucker, 2012). The p.D273Qfs*31 transcript is completely non-functional in yeast assays (Wydro, 2013; Maclean, 2018). In silico splice site analysis predicts that the c.815-27T>C alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Uncertain Significance
(Jan 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511195.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Converted during submission to Uncertain significance.
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Likely pathogenic
(Jun 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 21
Affected status: yes
Allele origin:
germline
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Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV001423626.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
Comment:
[ACMG/AMP: PS3, PP3, PP5, BS1] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein … (more)
[ACMG/AMP: PS3, PP3, PP5, BS1] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5], has an allele frequency that is greater than expected for the associated disease [BS1]. (less)
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Uncertain significance
(Aug 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 21
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV001736867.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Number of individuals with the variant: 1
Clinical Features:
Long palpebral fissure (present) , Intellectual disability (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Dysmetria (present) , Specific learning disability (present) , … (more)
Long palpebral fissure (present) , Intellectual disability (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Dysmetria (present) , Specific learning disability (present) , Gait ataxia (present) , Dysdiadochokinesis (present) , Intention tremor (present) , Gait imbalance (present) , Hyperglycinemia (present) , Difficulty walking (present) , Poor speech (present) , Hyper-beta-alaninemia (present) , Increased serum pyruvate (present) , Lacticaciduria (present) , Microtia (present) , Tension-type headache (present) , Abnormal fear-induced behavior (present) (less)
Age: 10-19 years
Sex: female
Ethnicity/Population group: Caucasians
Tissue: blood
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Uncertain significance
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 21
(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: SCV002768840.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0210 - Splice site variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with a known effect on protein structure. Functional studies showed three alternate transcripts were generated as a result of aberrant splicing from the allele with this variant: one transcript with normal splicing, one with exon 10 skipped resulting in a frameshift but no nonsense-mediated decay (NMD), and a third transcript that utilised a cryptic splice site resulting in a frameshift and NMD (PMIDs: 22072591, 32518176). (P) 0251 - Variant is heterozygous. (N) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (972 heterozygotes, 10 homozygotes). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. An allele harbouring this variant in cis with a second variant (p.(Gly56Arg)) has been reported as pathogenic in many patients, majority of whom were in compound heterozygous state with a pathogenic allele (PMIDs: 22072591, 25245479, 23553477). However, an allele harbouring this variant without the p.(Gly56Arg) variant has been associated with disease in one family (PMID: 32518176). (P) 1001 - Strong functional evidence supporting abnormal protein function. Functional studies showed levels of NUBPL mRNA and protein were decreased in the fibroblast cells heterozygous for this variant alone (PMID: 22072591). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Likely pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 21
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003810621.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 20, 2021)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 21
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001759967.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment on evidence:
In 2 sibs (patients 1A and 1B) with mitochondrial complex I deficiency nuclear type 21 (MC1DN21; 618242), Kimonis et al. (2021) identified compound heterozygosity for … (more)
In 2 sibs (patients 1A and 1B) with mitochondrial complex I deficiency nuclear type 21 (MC1DN21; 618242), Kimonis et al. (2021) identified compound heterozygosity for 2 mutations in the NUBPL gene: a c.815-27T-C transition (c.815-27T-C, NM_025152.3) in intron 9, predicted to cause splicing abnormalities, and a c.311T-C transition, resulting in a leu104-to-pro (L104P; 613621.0009) substitution. The mutations were identified by whole-exome sequencing, and the parents were shown to be mutation carriers. The L104P was reported in the gnomAD database at an allele frequency of 0.00023, and the c.815-27T-C mutation was reported in the gnomAD database at an allele frequency of 0.004476. The allele with the c.815-27T-C mutation was shown not to have the G56R mutation in cis (see 613621.0001), as had been seen in prior patients with the c.815-27T-C mutation. Splicing analysis in whole blood from the sibs showed that the c.815-27T-C mutation resulted in abnormal transcripts, with the 2 most abundant abnormal transcripts containing partial inclusion of intron 9 or skipping of exon 10. Expression of NUBPL with the L104P mutation in yeast showed that it resulted in decreased complex I levels compared to controls. (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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NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum. | Kimonis V | Journal of medical genetics | 2021 | PMID: 32518176 |
Pathogenic mutations in NUBPL affect complex I activity and cold tolerance in the yeast model Yarrowia lipolytica. | Maclean AE | Human molecular genetics | 2018 | PMID: 29982452 |
Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. | Haskell GT | Neurology. Genetics | 2018 | PMID: 29417091 |
Iron-sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery. | Maio N | Biochimica et biophysica acta | 2015 | PMID: 25245479 |
Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model. | Wydro MM | Disease models & mechanisms | 2013 | PMID: 23828044 |
NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern. | Kevelam SH | Neurology | 2013 | PMID: 23553477 |
Next-generation sequencing in molecular diagnosis: NUBPL mutations highlight the challenges of variant detection and interpretation. | Tucker EJ | Human mutation | 2012 | PMID: 22072591 |
High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. | Calvo SE | Nature genetics | 2010 | PMID: 20818383 |
Text-mined citations for rs118161496 ...
HelpRecord last updated May 01, 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.