ClinVar Genomic variation as it relates to human health
NM_018480.7(TMEM126B):c.635G>T (p.Gly212Val)
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(4); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018480.7(TMEM126B):c.635G>T (p.Gly212Val)
Variation ID: 236209 Accession: VCV000236209.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q14.1 11: 85636171 (GRCh38) [ NCBI UCSC ] 11: 85347215 (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 Sep 8, 2016 Apr 20, 2024 Sep 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018480.7:c.635G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060950.3:p.Gly212Val missense NM_001193537.3:c.575G>T NP_001180466.1:p.Gly192Val missense NM_001193538.3:c.545G>T NP_001180467.1:p.Gly182Val missense NM_001256546.2:c.545G>T NP_001243475.1:p.Gly182Val missense NM_001256547.2:c.497G>T NP_001243476.1:p.Gly166Val missense NM_001350393.1:c.410G>T NP_001337322.1:p.Gly137Val missense NR_146645.1:n.739G>T non-coding transcript variant NR_146646.1:n.567G>T non-coding transcript variant NC_000011.10:g.85636171G>T NC_000011.9:g.85347215G>T NG_053120.1:g.12599G>T - Protein change
- G212V, G137V, G192V, G166V, G182V
- Other names
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- Canonical SPDI
- NC_000011.10:85636170:G: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00076
The Genome Aggregation Database (gnomAD) 0.00103
The Genome Aggregation Database (gnomAD), exomes 0.00107
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00123
Exome Aggregation Consortium (ExAC) 0.00131
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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TMEM126B | - | - |
GRCh38 GRCh37 |
86 | 119 |
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
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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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May 18, 2016 | RCV000240617.2 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Aug 23, 2023 | RCV000239528.16 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 18, 2023 | RCV001269887.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 28, 2023 | RCV004017529.1 |
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
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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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Uncertain significance
(Apr 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 29
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000930284.1
First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019 |
Geographic origin: Iran
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Likely pathogenic
(Sep 11, 2018)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450221.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 29
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369031.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1,PP3.
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Pathogenic
(Dec 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 29
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819699.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: TMEM126B c.635G>T (p.Gly212Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: TMEM126B c.635G>T (p.Gly212Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 243948 control chromosomes. This frequency does not allow conclusions about variant significance. c.635G>T has been reported in the literature as biallelic homozygous or compound heterozygous genotype in multiple individuals affected with Mitochondrial Complex 1 Deficiency, Nuclear Type 29 (example, Sanchez-Caballero_2016, Alston_2016). 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 function (example, Alston_2016). The most pronounced variant effect results in 17% of normal complex I activity in a homozygous individual. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (P/LP, n=1; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 13, 2022)
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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: SCV002231740.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 212 of the TMEM126B protein (p.Gly212Val). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 212 of the TMEM126B protein (p.Gly212Val). This variant is present in population databases (rs141542003, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with complex I deficiency (PMID: 27374773, 27374774, 29093663). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236209). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 18, 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: SCV001787584.5
First in ClinVar: Aug 21, 2021 Last updated: Sep 30, 2023 |
Comment:
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: 27290639, … (more)
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: 27290639, 29093663, 27374773, 27374774, 30369941, 33726816, 35772644) (less)
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Likely pathogenic
(Aug 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 29
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016899.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 28, 2023)
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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: SCV004847303.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gly212Val variant in TMEM126B has been reported in 3 homozygous and 6 compound heterozygous individuals with Mitochondrial complex I deficiency and segregated with disease … (more)
The p.Gly212Val variant in TMEM126B has been reported in 3 homozygous and 6 compound heterozygous individuals with Mitochondrial complex I deficiency and segregated with disease in at least 2 affected family members from 2 families (Bird 2019 PMID: 31658717, Theunissen 2017 PMID: 29093663, Sanchez-Caballero 2016 PMID: 27374773, Alston 2016 PMID: 27374774). This variant has also been identified in 0.18% (121/68028) European chromosomes by gnomAD v3.1.2 (https://gnomad.broadinstitute.org/). It has also been reported in ClinVar (Variation ID 236209). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro and in vivo functional studies, including using patient fibroblasts, support an impact on protein function (Sanchez-Caballero 2016 PMID: 27374773, Alston 2016 PMID: 27374774, Theunissen 2017 PMID: 29093663). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Mitochondrial complex I deficiency. ACMG/AMP criteria applied: PM3_Very_Strong, PS3_Moderate, PP1 (less)
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Pathogenic
(May 18, 2016)
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no assertion criteria provided
Method: clinical testing
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Mitochondrial disease
Affected status: yes
Allele origin:
germline
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Wellcome Centre for Mitochondrial Research, Newcastle University
Accession: SCV000280579.1
First in ClinVar: Sep 08, 2016 Last updated: Sep 08, 2016 |
Number of individuals with the variant: 6
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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 29
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000297964.2
First in ClinVar: Aug 22, 2016 Last updated: Dec 16, 2018 |
Comment on evidence:
In 2 unrelated adult patients of European descent with mitochondrial complex I deficiency nuclear type 29 (MC1DN29; 618250), Sanchez-Caballero et al. (2016) identified compound heterozygous … (more)
In 2 unrelated adult patients of European descent with mitochondrial complex I deficiency nuclear type 29 (MC1DN29; 618250), Sanchez-Caballero et al. (2016) identified compound heterozygous mutations in the TMEM126B gene: a c.635G-T transversion (rs141542003) in exon 5, resulting in a gly212-to-val (G212V) substitution, and a c.397G-A transition in exon 3, predicted to result in an asp133-to-asn (D133N; 615533.0002) substitution. However, RT-PCR analysis showed that the c.397G-A variant led to the loss of a splice site, the skipping of exon 3, and a truncated cDNA with reduced stability. The mutations, which were found by whole-exome sequencing in 1 family and by targeted exome sequencing in the second family, were confirmed by Sanger sequencing and filtered against the dbSNP, 1000 Genomes Project, and Exome Variant Server databases and an in-house database. Both mutations were found at low frequencies in the dbSNP and ExAC databases. A third patient with a similar disorder was compound heterozygous for the G212V substitution and a c.208C-T transition in exon 3, resulting in a gln70-to-ter (Q70X; 615533.0003) substitution. All mutations segregated with the disorder in the 3 families. Alston et al. (2016) identified homozygosity for the c.635G-T mutation (SCV000280579) in 2 unrelated patients with MC1DN29. One had onset of exercise intolerance in childhood, whereas the other had a more complex phenotype with early onset renal tubular acidosis and hypertrophic cardiomyopathy. Four patients from 2 additional families with MC1DN29, manifest as exercise intolerance, muscle weakness, and myalgia, were compound heterozygous for c.635G-T and a 1-bp deletion (c.401delA; 615533.0004), resulting in a frameshift and premature termination (Asn134IlefsTer2). The c.401delA mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases, whereas the c.635G-T mutation was found at low frequencies in all 3 databases. The G212V mutation affects a moderately conserved residue predicted to lie within a helical domain, where it likely affects the tertiary structure. Haplotype analysis showed a founder effect for both mutations. Patient cells showed a marked reduction of fully assembled complex I with an accumulation of assembly intermediates. These defects were rescued by wildtype TMEM126B. There were tissue-specific differences in the effects of the mutations: some patient-derived fibroblasts showed decreased complex I activity, whereas others had normal complex I activity. The mutations segregated with the disorder in all families. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552840.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TMEM126B p.G212V variant was identified in the literature in ten patients (eight families) with mitochondrial complex I deficiency; three patients were homozygous for the … (more)
The TMEM126B p.G212V variant was identified in the literature in ten patients (eight families) with mitochondrial complex I deficiency; three patients were homozygous for the p.G212V variant and seven patients were compound heterozygous (Alston_2016_PMID: 27374774; S√°nchez-Caballero_2016_PMID:27374773; Theunissen_2017_PMID:29093663). Varying degrees of clinical symptoms were observed, ranging from mild exercise intolerance to muscle weakness causing patients to be wheelchair bound (two compound heterozygotes) and multiorgan involvement manifesting in infancy including respiratory failure, cardiomyopathy and renal acidosis (one homozygote). The variant was identified in dbSNP (ID: rs141542003) and ClinVar (classified as uncertain significance by Genomic Research Center, Shahid Beheshti University of Medical Sciences and as pathogenic by Wellcome Centre for Mitochondrial Research, Newcastle University). The variant was identified in control databases in 295 of 275284 chromosomes at a frequency of 0.001072 increasing the likelihood this could be a low frequency benign variant, however no homozygotes were observed (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 241 of 127066 chromosomes (freq: 0.001897), Other in 11 of 7042 chromosomes (freq: 0.001562), European (Finnish) in 33 of 24838 chromosomes (freq: 0.001329), African in 4 of 24824 chromosomes (freq: 0.000161), Latino in 5 of 33066 chromosomes (freq: 0.000151) and South Asian in 1 of 28936 chromosomes (freq: 0.000035), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.G212 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies of patient muscle and fibroblast cell lines demonstrated decreased complex I levels in compound heterozygous patients (Alston_2016_PMID: 27374774). Decreased complex I activity was observed in all homozygous patient muscle cell lines, however decreased OXPHOS capacity or complex I activity and incomplete complex I assembly were observed in only two homozygote fibroblasts while the third homozygote had normal complex I activity in fibroblasts (Alston_2016_PMID: 27374774; Theunissen_2017_PMID:29093663). This data suggests that the p.G212V variant plays a functional role however it does not completely abolish complex I activity and likely leads to a mild phenotype; other factors may influence functional and clinical manifestations. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. (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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Oxygraphy Versus Enzymology for the Biochemical Diagnosis of Primary Mitochondrial Disease. | Bird MJ | Metabolites | 2019 | PMID: 31658717 |
Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause. | Theunissen TEJ | Frontiers in genetics | 2018 | PMID: 30369941 |
Selection and Characterization of Palmitic Acid Responsive Patients with an OXPHOS Complex I Defect. | Theunissen TEJ | Frontiers in molecular neuroscience | 2017 | PMID: 29093663 |
Biallelic Mutations in TMEM126B Cause Severe Complex I Deficiency with a Variable Clinical Phenotype. | Alston CL | American journal of human genetics | 2016 | PMID: 27374774 |
Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency. | Sánchez-Caballero L | American journal of human genetics | 2016 | PMID: 27374773 |
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. | Pronicka E | Journal of translational medicine | 2016 | PMID: 27290639 |
Text-mined citations for rs141542003 ...
HelpRecord last updated May 08, 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.