rs141542003

Positions:

chr11-85636171-G-T

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1

Conservation

PhyloP100: 2.44

Variant links:

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 links:

Genome browser will be placed here

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: {Uncertain_significance=1, Likely_pathogenic=3, 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	UniProt
TMEM126B	NM_018480.7 linkuse as main transcript	c.635G>T	p.Gly212Val	missense_variant	5/5	ENST00000358867.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM126B	ENST00000358867.11 linkuse as main transcript	c.635G>T	p.Gly212Val	missense_variant	5/5	2	NM_018480.7	P1	Q8IUX1-1

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

148

AN:

152086

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00107

AC:

262

AN:

243948

Hom.:

AF XY:

0.00111

AC XY:

146

AN XY:

132024

show subpopulations

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 SAS exome

AF:

0.0000346

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.:

Cov.:

AF XY:

0.00145

AC XY:

1046

AN XY:

723204

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.0000949

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000473

Gnomad4 FIN exome

AF:

0.00137

Gnomad4 NFE exome

AF:

0.00182

Gnomad4 OTH exome

AF:

0.000933

GnomAD4 genome

AF:

0.000973

AC:

148

AN:

152086

Hom.:

Cov.:

AF XY:

0.000875

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00147

Hom.:

Bravo

AF:

0.000756

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00128

AC:

156

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

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 13, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 23, 2023	- -
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	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. -

not provided

Pathogenic:4

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	Sep 18, 2023	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) -
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; SâˆšÂ°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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

.;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.7

.;M

MutationTaster

Benign

0.89

D;D;D

PrimateAI

Benign

0.38

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

GERP RS

4.1

Varity_R

0.59

gMVP

0.65

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over