Submissions for variant NM_018480.7(TMEM126B):c.635G>T (p.Gly212Val)

gnomAD frequency: 0.00103  dbSNP: rs141542003

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000239528	SCV000930284	uncertain significance	Mitochondrial complex 1 deficiency, nuclear type 29	2019-04-27	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000239528	SCV001369031	likely pathogenic	Mitochondrial complex 1 deficiency, nuclear type 29	2019-06-26	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1,PP3.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269887	SCV001450221	likely pathogenic	not provided	2018-09-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001269887	SCV001787584	pathogenic	not provided	2024-05-14	criteria provided, single submitter	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: 27290639, 29093663, 27374773, 27374774, 30369941, 33726816, 35772644)
Revvity Omics, Revvity	RCV000239528	SCV002016899	likely pathogenic	Mitochondrial complex 1 deficiency, nuclear type 29	2023-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001269887	SCV002231740	pathogenic	not provided	2022-10-13	criteria provided, single submitter	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). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000239528	SCV002819699	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 29	2022-12-20	criteria provided, single submitter	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017529	SCV004847303	pathogenic	Mitochondrial complex I deficiency	2023-07-28	criteria provided, single submitter	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
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000240617	SCV000280579	pathogenic	Mitochondrial disease	2016-05-18	no assertion criteria provided	clinical testing
OMIM	RCV000239528	SCV000297964	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 29	2018-12-13	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001269887	SCV001552840	likely pathogenic	not provided		no assertion criteria provided	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.