rs141542003
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4
The NM_018480.7(TMEM126B):c.635G>T(p.Gly212Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,605,814 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 3 hom. )
Consequence
TMEM126B
NM_018480.7 missense
NM_018480.7 missense
Scores
3
8
8
Clinical Significance
Conservation
PhyloP100: 2.44
Genes affected
TMEM126B (HGNC:30883): (transmembrane protein 126B) This gene encodes a mitochondrial transmembrane protein which is a component of the mitochondrial complex I assembly complex. The encoded protein serves as an assembly factor that is required for formation of the membrane arm of the complex. It interacts with NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 13. Naturally occurring mutations in this gene are associated with isolated complex I deficiency. A pseudogene of this gene has been defined on chromosome 9. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP5
Variant 11-85636171-G-T is Pathogenic according to our data. Variant chr11-85636171-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 236209.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=4}. Variant chr11-85636171-G-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.17585585). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TMEM126B | NM_018480.7 | c.635G>T | p.Gly212Val | missense_variant | 5/5 | ENST00000358867.11 | NP_060950.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TMEM126B | ENST00000358867.11 | c.635G>T | p.Gly212Val | missense_variant | 5/5 | 2 | NM_018480.7 | ENSP00000351737 | P1 |
Frequencies
GnomAD3 genomes 0.000973 AC: 148AN: 152086Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00107 AC: 262AN: 243948Hom.: 0 AF XY: 0.00111 AC XY: 146AN XY: 132024
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GnomAD4 exome AF: 0.00149 AC: 2159AN: 1453728Hom.: 3 Cov.: 31 AF XY: 0.00145 AC XY: 1046AN XY: 723204
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GnomAD4 genome 0.000973 AC: 148AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.000875 AC XY: 65AN XY: 74282
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:10Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 29 Pathogenic:4Uncertain:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 13, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jun 26, 2019 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1,PP3. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2022 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 23, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Apr 27, 2019 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | 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. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 11, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 14, 2024 | 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) - |
Mitochondrial complex I deficiency Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 28, 2023 | 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 - |
Mitochondrial disease Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | May 18, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MVP
MPC
0.29
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at