rs200800978

Variant names:

• chr2-201085526-G-T
• rs200800978
• NM_002491.3:c.208G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002491.3(NDUFB3):​c.208G>T​(p.Gly70*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,612,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: NDUFB3 NM_002491.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 8.47

Genes affected

NDUFB3 (HGNC:7698): (NADH:ubiquinone oxidoreductase subunit B3) This gene encodes an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which is the first enzyme in the electron transport chain of mitochondria. This protein localizes to the inner membrane of the mitochondrion as a single-pass membrane protein. Mutations in this gene contribute to mitochondrial complex 1 deficiency. Alternative splicing results in multiple transcript variants encoding the same protein. Humans have multiple pseudogenes of this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.3 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-201085526-G-T is Pathogenic according to our data. Variant chr2-201085526-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39836.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=3}. Variant chr2-201085526-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB3	NM_002491.3	c.208G>T	p.Gly70*	stop_gained	Exon 3 of 3	ENST00000237889.9	NP_002482.1
NDUFB3	NM_001257102.2	c.208G>T	p.Gly70*	stop_gained	Exon 4 of 4		NP_001244031.1
NDUFB3	XM_011511230.4	c.208G>T	p.Gly70*	stop_gained	Exon 4 of 4		XP_011509532.1
NDUFB3	XM_047444488.1	c.208G>T	p.Gly70*	stop_gained	Exon 4 of 4		XP_047300444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB3	ENST00000237889.9	c.208G>T	p.Gly70*	stop_gained	Exon 3 of 3	1	NM_002491.3	ENSP00000237889.4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151756 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 251020 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135664

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000160 AC: 233 AN: 1460588 Hom.: 0 Cov.: 32 AF XY: 0.000158 AC XY: 115 AN XY: 726622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151874 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74182

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000657

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Jul 02, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the NDUFB3 gene demonstrated a sequence change, c.208G>T, which results in the creation of a premature stop codon at amino acid position 70, p.Gly70*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated NDUFB3 protein with potentially abnormal function. This sequence change has previously been described in a patient with isolated complex I deficiency along with another missense variant in this gene, and functional studies were performed to demonstrate pathogenicity (Haack et al., 2012). The phenotypic presentation included mitochondrial encephalopathy, mitochondrial myopathy, muscular hypotonia, developmental delay and lactic acidosis. These collective evidences indicate that this sequence change is likely pathogenic. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NDUFB3 p.Gly70* variant was identified as a compound heterozygous variant in individuals with mitochondrial complex I deficiency; functional studies in fibroblasts from this patient demonstrated low complex I activity (Haack_2012_PMID:22499348). The variant was identified in dbSNP (ID: rs200800978) and ClinVar (classified as likely pathogenic by GeneDx and as pathogenic by Ambry Genetics). The variant was identified in control databases in 31 of 282238 chromosomes at a frequency of 0.0001098 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 24 of 128702 chromosomes (freq: 0.000187), Latino in 5 of 35410 chromosomes (freq: 0.000141), Other in 1 of 7204 chromosomes (freq: 0.000139) and South Asian in 1 of 30608 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The c.208G>T variant leads to a premature stop codon at position 70, which is predicted to lead to a truncated or absent protein and loss of function in homozygous individuals. Loss of function variants in the NDUFB3 gene are an established mechanism of disease for mitochondrial complex I deficiency and are the type of variant expected to cause the disorder when found in homozygous or compound heterozygous individuals. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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. -

Jul 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, specifically expression of NDUFB3 cDNA with either the p.W22R or p.G70X variants failed to rescue the complex I deficiency in patient fibroblasts (Haack et al., 2012); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 33233646, 26795593, 31589614, 22499348) -

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly70*) in the NDUFB3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the NDUFB3 protein. This variant is present in population databases (rs200800978, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 22499348, 26795593). ClinVar contains an entry for this variant (Variation ID: 39836). Studies have shown that this premature translational stop signal alters NDUFB3 gene expression (PMID: 22499348). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mitochondrial complex 1 deficiency, nuclear type 25 Pathogenic:2

Apr 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 26, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Aug 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.208G>T (p.G70*) alteration, located in exon 3 (coding exon 2) of the NDUFB3 gene, consists of a G to T substitution at nucleotide position 208. This changes the amino acid from a glycine (G) to a stop codon at amino acid position 70. This alteration occurs at the 3' terminus of the NDUFB3 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29.6% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the T allele has an overall frequency of 0.011% (31/282238) total alleles studied. The highest observed frequency was 0.019% (24/128702) of European (non-Finnish) alleles. This variant has been identified in conjunction with another NDUFB3 variant in an individual with features consistent with complex I deficiency (Haack, 2012; Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.49
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs200800978; hg19: chr2-201950249;