rs141542003

Variant names:

• chr11-85636171-G-T
• rs141542003
• NM_018480.7:c.635G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 8P and 6B. PP5_Very_Strong BP4 BS1_Supporting BS2

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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: TMEM126B NM_018480.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 2.44
• Publications: 21 publications found

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]

TMEM126B Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 29

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 11-85636171-G-T is Pathogenic according to our data. Variant chr11-85636171-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 236209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17585585). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000973 (148/152086) while in subpopulation NFE AF = 0.00178 (121/68028). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM126B	NM_018480.7	c.635G>T	p.Gly212Val	missense_variant	Exon 5 of 5	ENST00000358867.11	NP_060950.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM126B	ENST00000358867.11	c.635G>T	p.Gly212Val	missense_variant	Exon 5 of 5	2	NM_018480.7	ENSP00000351737.7

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00107 AC: 262 AN: 243948 AF XY: 0.00111

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00149 AC: 2159 AN: 1453728 Hom.: 3 Cov.: 31 AF XY: 0.00145 AC XY: 1046 AN XY: 723204

African (AFR) AF: 0.000151 AC: 5 AN: 33090

American (AMR) AF: 0.0000949 AC: 4 AN: 42164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.0000473 AC: 4 AN: 84570

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53176

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.00182 AC: 2016 AN: 1109656

Other (OTH) AF: 0.000933 AC: 56 AN: 60046

GnomAD4 genome AF: 0.000973 AC: 148 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.000875 AC XY: 65 AN XY: 74282

African (AFR) AF: 0.000338 AC: 14 AN: 41408

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.000756

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00128 AC: 156

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 29 Pathogenic:5

Jun 26, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1,PP3. -

Dec 13, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 03, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 23, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4 Other:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. For these reasons, this variant has been classified as Pathogenic. -

Sep 11, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 31658717, 27290639, 29093663, 27374773, 27374774, 30369941, 33726816, 37734845, 35772644) -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as not provided and reported on 11-14-2023 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Mitochondrial complex I deficiency Pathogenic:1

Jul 28, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 18, 2016

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.7	.;M
PhyloP100		2.4
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.60
MVP		0.33
MPC		0.29
ClinPred		0.097	T
GERP RS		4.1
Varity_R		0.59
gMVP		0.65
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141542003; hg19: chr11-85347215; COSMIC: COSV99074303; COSMIC: COSV99074303;