rs207460004

Variant names:

• chrM-14849-T-C
• rs207460004
• unassigned_transcript_4818:c.103T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: CYTB missense
• Scores: Apogee2 Pathogenic 0.87
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2 EXIT-/-Septo-Optic-Dysplasia
• Conservation: PhyloP100: 5.74

Genes affected

CYTB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTB	unassigned_transcript_4818	c.103T>C	p.Ser35Pro	missense_variant	Exon 1 of 1
ND6	unassigned_transcript_4816	c.-176A>G		upstream_gene_variant
TRNE	unassigned_transcript_4817	c.-107A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Alfa AF: 0.000106 Hom.: 0

Mitomap

EXIT-/-Septo-Optic-Dysplasia

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Exercise intolerance, cardiomyopathy, and septooptic dysplasia Pathogenic:1

Mar 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leigh syndrome Uncertain:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.14849T>C (YP_003024038.1:p.Ser35Pro) variant in MTCYB gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PP6, PP7 -

Mitochondrial disease Uncertain:1

Jun 30, 2022

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.14849T>C (p.S35P) variant in MT-CYB has been reported in two unrelated men. The first reported individual had developmental delay, microcephaly, lactic acidosis and rhabdomyolysis with illness, short stature, dysdiadokinesia, ataxia, exercise intolerance, fatigue, Wolff-Parkinson-White, left ventricular hypertrophy, retinitis pigmentosa, septo-optic dysplasia, and cerebellar hypoplasia (PMID: 11891837) and the second reported individual had exercise intolerance, depressive episodes, and myopathy with ragged red fibers seen on muscle biopsy (PMID: 20544923). Both individuals had onset of features in childhood and heteroplasmy levels in various tissues ranged from 6-85%. Haplogroup information was not reported for all cases precluding consideration for PS4. The variant was reported de novo in the first case report as it was absent in mother’s blood (PMID: 11891837), however no additional tissues were tested and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.74 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on May 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.87
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs207460004; hg19: chrM-14850;