ENST00000361789.2:c.103T>C

Variant names:

• chrM-14849-T-C
• rs207460004
• ENST00000361789.2:c.103T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120623/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CYB ENST00000361789.2 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
• Publications: 14 publications found

Genes affected

MT-CYB (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]

MT-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)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

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

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361789.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CYB	ENST00000361789.2	TSL:6	c.103T>C	p.Ser35Pro	missense	Exon 1 of 1	ENSP00000354554.2	P00156
	MT-ND6	ENST00000361681.2	TSL:6	c.-176A>G		upstream_gene	N/A	ENSP00000354665.2	P03923
	MT-TE	ENST00000387459.1	TSL:6	n.-107A>G		upstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.0000217 Hom.: 0

Mitomap

Disease(s): EXIT-/-Septo-Optic-Dysplasia

Status: Cfrm-[VUS*]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Exercise intolerance, cardiomyopathy, and septooptic dysplasia (1)
-	1	-	Leigh syndrome (1)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.87
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	0.76
PhyloP100		5.7

Other links and lift over

dbSNP: rs207460004; hg19: chrM-14850;