M-14849-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PM2_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
Consequence
ENST00000361789.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYTB | CYTB.1 use as main transcript | c.103T>C | p.Ser35Pro | missense_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-CYB | ENST00000361789.2 | c.103T>C | p.Ser35Pro | missense_variant | 1/1 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Exercise intolerance, cardiomyopathy, and septooptic dysplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2002 | - - |
Mitochondrial disease Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jun 30, 2022 | 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. - |
Leigh syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 17, 2019 | 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 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at